Role of histamine in the regulation of intestinal immunity in fish

Accepted Manuscript Role of histamine in the regulation of intestinal immunity in fish Jorge Galindo-Villegas, Erick Garcia-Garcia, Victoriano Mulero PII:

S0145-305X(16)30037-4

DOI:

10.1016/j.dci.2016.02.013

Reference:

DCI 2559

To appear in:

Developmental and Comparative Immunology

Received Date: 15 December 2015 Revised Date:

2 February 2016

Accepted Date: 8 February 2016

Please cite this article as: Galindo-Villegas, J., Garcia-Garcia, E., Mulero, V., Role of histamine in the regulation of intestinal immunity in fish, Developmental and Comparative Immunology (2016), doi: 10.1016/j.dci.2016.02.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Role of histamine in the regulation of intestinal immunity in fish

2 3 4 Jorge Galindo-Villegas1,*, Erick Garcia-Garcia1 and Victoriano Mulero1,*

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Campus Universitario de Espinardo, Murcia 30100, Spain

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Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, IMIB-Arrixaca,

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Corresponding authors. Address: 1Department of Cell Biology and Histology, Faculty of Biology.

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University of Murcia. Campus Universitario de Espinardo. 30100 Murcia, Spain. Phone: +34 868 887581.

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Fax: +34 868 883963. E-mail addresses: [email protected] (J.G.-V.), [email protected] (V.M.)

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Running title: Histamine regulates fish immunity

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Highlights

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The inflammatory response at different levels in the gut is directly regulated by the action of histamine.




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In fish, immunologically active histamine has been demonstrated only in Perciformes, the most evolutionarily advanced order of teleost.




Despite several efforts, the molecular basis and exact role of this biogenic amine in perciforms is still a matter of debate.




Possible roles for the activity of histamine and mast cells in fish GALT are proposed.

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characterized.

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In mammals, crosstalk between the immune system and histamine produced by mast cells is fairly

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ABSTRACT

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Total count 166 words In mammals, during the acute inflammatory response, the complex interrelationship and cross-talk

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among histamine and the immune system has been fairly well characterized. There is a substantial body

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of information on its structure, metabolism, receptors, signal transduction, physiologic and pathologic

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effects. However, for early vertebrates, there is little such knowledge. In the case of teleost fish, this lack

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of knowledge has been due to the widely held belief that histamine is not present in this phylogenetic

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group. However, it has been recently demonstrated, that granules of mast cells in perciforms contain

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biologically active histamine. More importantly, the inflammatory response was clearly demonstrated to

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be regulated by the direct action of histamine on professional phagocytes. Nevertheless, the molecular

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basis and exact role of this biogenic amine in perciforms is still a matter of speculation. Therefore, this

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review intends to summarize recent experimental evidence regarding fish mast cells and correlate the

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same with their mammalian counterparts to establish the possible role of histamine in the fish intestinal

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inflammatory response.

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Keywords: Eosinophilic granule cell, Fish, GALT, Histamine, Immunity, Inflammation, Mast cells,

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Perciforms

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Introduction During an inflammatory response in the vertebrate gut, immediate changes in the local mucosal

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tissue encompass a tightly regulated process often related with a large number of systemic changes,

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commonly referred to as the acute phase response (APR). The APR in mucosal tissues is presumed to

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play a key defensive role, which in normal circumstances, results in transient protection from infection

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while generating long term tolerance against innocuous antigens (Beck et al., 2002). In the gut, an

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impressive repertoire of immunological mediated events take place, with pathogenic disruption and

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trauma at the top of the list of stimuli triggering an immediate APR (Gilroy and De Maeyer, 2015; Winter

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et al., 2010). Two major immunogenic sites can be distinguished in the mammalian gut mucosal immune

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system: an induction site comprised by gut-associated lymphoid tissue (GALT) encompassing Peyer’s

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patches and mesenteric lymph nodes, and the effector sites: the lamina propria (LP) and the intraepithelial

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lymphocyte (IEL) compartment (Magrone and Jirillo, 2013; Rombout et al., 2011). In contrast, in early

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vertebrates like the teleost fish, GALT consists of diffuse elements and lacks the organized induction sites

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present in endotherms (Salinas et al., 2015). However, as in the case of mammalian effectors the teleost

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gut harbors two main populations of immune cells: lamina propria leukocytes (LPLs), which include a

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variety of effector cells, such as macrophages, granulocytes, dendritic cells, lymphocytes, and plasma

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cells; and the intraepithelial lymphocytes (IEL), composed mostly of T cells and a few B cells located

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among epithelial cells (Galindo-Villegas et al., 2013; Parra et al., 2015; Salinas and Parra, 2015).

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Interestingly, despite their scattered localization this set of immune competent cells inhabiting the fish gut

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has the capacity to mount a strong protective APR while limiting self-tissue damage (Galindo-Villegas et

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al., 2012). As a result of their wide protective activity and plasticity, attempts have been made to

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characterize the full set of immune competent cells present in the intestinal epithelium and lamina propria

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of many fish species. Using Carboxypeptidase A5, a MC-specific enzyme differential heterogeneous

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morphology, granule content, sensitivity to fixatives and response to drugs has been revealed in granular

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cells, which resemble that seen in the mammalian mast cells (MCs) (Dobson et al., 2008). Heterogeneity

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is represented in fish by a wide variation in the distribution (Reite and Evensen, 2006), staining properties

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(Vallejo and Ellis, 1989), abundance (Dezfuli et al., 2015a; Lauriano et al., 2012) or even existence (Reite,

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2005) of this particular cell type among species. Despite the metachromatic heterogeneity observed in

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MCs and/or eosinophilic granule cells (EGCs) of teleost fish, most published results indicate that

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MCs/EGCs in teleost fish are mast cells of the mucosal mast cell type (Reite, 1998). Therefore, herein we

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use the term MCs instead of the mixed term MCs/EGCs. Although confusing, there is general agreement

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that the main functional roles, as exploited in immunity, are quite similar in many teleost fish families,

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such as the cichlidae (Matsuyama and Iida, 1999), pleuronectidae (Murray et al., 2003), salmonidae

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(Dorin et al., 1993; Vallejo and Ellis, 1989), erythrinidae (Rocha and Chiarini-Garcia, 2007; Vicha and

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Schmale, 1994), cyprinidae (Balla et al., 2010; Da’as et al., 2011; Dezfuli et al., 2015a, 2012b, 2011b;

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Reite, 1965), pomacentridae (Schmale et al., 2004), moronidae (Mulero et al., 2007), percidae (Corrales

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et al., 2010; Dezfuli et al., 2015b; Mulero et al., 2007) or siluridae (Dezfuli et al., 2011a). A possible

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explanation for this observed plasticity is that all MCs have a hematopoietic origin, but derive from

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distinct precursors, differentiating into their permanent phenotype once stablished in their homing

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mucosal tissue (Rodewald et al., 1996; Yamaguchi et al., 2013). MCs are key regulatory cells for the

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survival of most vertebrates, where they act as professional immune sentinels, coordinating and

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integrating many branches of the innate immune system. Once MCs detect diverse pathogens, other

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activated host cells, damaged tissue, complement system activation or several other signals derived from

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the external environment, depending on the balance of activating stimuli, they respond by typical

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degranulation releasing a panel of inflammatory mediators including but not limited to different

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proteolytic enzymes, cytokines, chemokines, growth factors, reactive oxygen and nitrogen species,

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arachidonic acid metabolites and histamine (Csaba, 2015; Dezfuli and Giari, 2008; Oskeritzian, 2012;

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Reber et al., 2015) (Fig. 1). Of particular interest in this review would be the histamine

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[2-(4-imidazolyl)-ethylamine], which is a short-acting endogenous amine, synthesized by the enzyme

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histidine decarboxylase and produced by a wide set of cell types widely distributed in most mucosal

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tissues throughout the body of some fish, reptiles, birds and mammals (Baccari et al., 2011). Histamine

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exerts a range of effects on many physiologic and pathologic processes, but the best characterized are

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those involved in inflammation, gastric acid secretion and as neurotransmitters. Evolutionarily, histamine

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seems to be a well conserved feature of the immune system, and its presence and defensive functions

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have been demonstrated in invertebrates which appeared approximately 500 million years ago (Crivellato

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et al., 2015). In mammals, MCs, basophils, gastric enterochromaffin-like cells, and histaminergic neurons

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are the best described cellular sources of histamine, but other cell types, for example platelets, dendritic

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and T cells, can also stimulated into producing it (Smolinska et al., 2014). However, among all possible

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cellular sources in any taxon only MCs have the ability to replenish and store in their granules the

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histamine synthesized de novo during an infection or after its resolution (Abraham and St John, 2010).

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Therefore, several functional complex relationships and intrinsic cross-talk through specific receptors

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have been fairly well characterized between histamine and the many cell types involved in the regulation

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of mammalian innate and adaptive immunity (Ferstl et al., 2012). Additionally, new findings suggest that

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innate lymphoid cells (ILCs), which are a growing family of immune cells that mirror the phenotypes and

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functions of T cells, could also be modulated by histamine, particularly the type2 (ILC2) family (Morita

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et al., 2015). Mechanistically, ILC2 cells seems to play a critical role in the protection against intestinal

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helminthic infection acting through a negative-feedback regulation of the canonical type 2 cytokines IL-5,

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IL-9 and IL-13 in response to IL-25 and IL-33, which, in turn, promotes mucus over production by goblet

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cells, and the expansion and recruitment of mucosal MCs following histamine degranulation, resulting in

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hypermotility and contraction of smooth muscle and blood vessels (Licona-Limón et al., 2013). In

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contrast to mammals, ILC2 has not been reported in fish so far, and, the presence of histamine in this

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phylogenetic group is a particular feature exclusively reserved to the most evolutionarily advanced order

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of teleost, the Perciformes (Mulero et al., 2007). Thus, even though the presence of ILCs in fish cannot be

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ruled out, the regulation of the inflammatory response in their gut mucosa by histamine seems to be

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carried out through the proliferation of leukocytes in lympho-hematopoietic organs, the recruitment of

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innate and adaptive immunity elements into the intestines via blood circulation, and the control of specific

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functional features in leukocytes (Estensoro et al., 2014; Mulero et al., 2007). Additionally, the diverse

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biological effects of histamine are mediated through a limited number of different specialized histamine

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receptors (Huang and Thurmond, 2008). Whatever the case, our present understanding of histamine in the

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regulation of the fish intestinal inflammatory response is far from complete. Thus, in this review we

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intend to summarize the recent evidence gathered for the effect of histamine and cross-talk with the

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immune system, on the mucosal epithelium and include a fresh description of how this molecule affects

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the fish intestinal inflammatory response.

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2.

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Fish gut-associated lymphoid tissue (GALT). In any host, immunity acts at different levels. For example, as has been extensively described, all

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metazoans present a mucosal epithelium specialized in sensing danger signals and mounting an

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immediate innate immune response. Fish particularly, have developed complex means and key structures

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located selectively along their bodies to orchestrate coordinate inflammatory reactions and support large

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societies of microbial partners by establishing mutualistic relationships with hundreds of microorganisms.

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Surprisingly, they have the same conformational, molecular, or locomotive structures as closely related

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pathogens that bombard permanently their mucosal epithelial barriers (Galindo-Villegas et al., 2012; 6

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Montalban-Arques et al., 2015). Collectively, such structures comprise the mucosa-associated lymphoid

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tissue (MALT), one of the oldest and most universal modules of innate immunity. MALT is represented

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in fish by four different tissue complexes, the gill-associated lymphoid tissue (GiALT), skin-associated

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lymphoid tissue (SALT), nasopharynx-associated lymphoid tissue (NALT), and gut-associated lymphoid

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tissue (GALT) (Salinas, 2015). For more complete information on fish mucosal immunology structures

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and functions, see: (Lazado and Caipang, 2014; Parra et al., 2015; Rombout et al., 2014, 2011; Salinas,

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2015; Tacchi et al., 2014).

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The study of fish GALT deserves special attention by fish immunologists as well as the fish farming industry, because this long mucosal tract divided into segments, each with particular characteristics,

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(Murashita et al., 2008; Rombout et al., 2011; Ballesteros et al., 2013; Løkka et al., 2013), contains a

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changing mix of mutualistic microflora, pathogens, foreign antigens and nutrients throughout the fish life

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time. Together, these characteristics open a huge runway for selective manipulation that, if correctly

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orchestrated and applied at a timely moment, may improve the fish immune status (Montalban-Arques et

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al., 2015). Studies conducted in carp Cyprinus carpio and rainbow trout Oncorhynchus mykiss were the

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first to show that fish GALT is composed of IEL, plasma cells, granulocytes and resident macrophages,

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some located among epithelial cells while others are disseminated throughout the LP (Pérez et al., 2010;

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Picchietti et al., 2009). Additionally, the same researchers observed that in fish intestinal mucosa antigen

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uptake is performed by enterocytes, before being transported to macrophages where they process and

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present it to lymphoid cells through classical antigen presentation mechanisms (Georgopoulou and

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Vernier, 1986; Rombout et al., 1993). In this process, MCs have been well-recognized in many fish

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species as the master component in orchestrating immunity by starting or controlling the APR (Baccari et

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al., 2011; Dezfuli et al., 2015a, 2015b, 2012b; Hellberg et al., 2013; Manera et al., 2011) (Fig. 1).

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However, recently, a possible novel association between MCs and goblet cells (GCs) has attracted

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attention due the critical functions of both in the fish intestine. GCs are specialized in secreting the mucus

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hydrogel, which is predominantly made up of mucins that lines the epithelia of the gastrointestinal tract to

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keep microbes at bay, not only through mucus production but also by enforcing the degranulation of MCs

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around the site of parasite attachment, influencing the microbiota distribution and content while enabling

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the passage of nutrients and oxygen (Dezfuli et al., 2015a; Jevtov et al., 2014; Kim and Khan, 2013). The

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mucins, long thread-like polymers that are densely O-glycosylated, can be divided structurally into two

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distinct families, the large secreted gel-forming form, and membrane bound form (Corfield, 2015).

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Among both families, at least 20 mucins genes (MUC1 to 20) have been identified and characterized in

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the vertebrate lineage. Notably, mucin 2 (MUC2) is particularly prominent in the gut where it is secreted

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from GCs to cover the intestinal epithelium and form a two-tier inner and outer layer that prevents

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bacterial adhesion (Johansson et al., 2011; Pelaseyed et al., 2014) (Fig. 2). While the inner dense mucous

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layer restricts bacterial penetration and growth, the extended outer layer forms an environment that is

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well-suited to resident bacteria (Johansson et al., 2011). Interestingly, a recent comprehensive overview

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of the mucin gene family of gilthead seabream (Sparus aurata) revealed the tissue-specific expression

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pattern in the gut of this fish (Pérez-Sánchez et al., 2013). The findings provided evidence for the

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constitutive expression of Muc18 in the stomach, Muc13 in the antero-posterior intestine, and Muc2

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throughout the intestine with a particular dominance in the hind gut. In a different study, live imaging of

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zebrafish (Danio rerio) larvae showed that Muc2.1 shares its tissue localization with human MUC2, the

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major mucin in the gut (Jevtov et al., 2014). These results suggest the active participation of Muc2 in

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restraining intestinal microflora and avoiding the triggering of an immune APR. However, mucus

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producing cells are not enough to defend host integrity and a vast number of different leucocytes are

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required to mount an organized immune reaction, and hence inflammation (Fig. 2). Many immune cell

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types and factors contribute to helminthes clearance from mammalian GALT (Maizels et al., 2012). But,

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mucus production which facilitates the physical flushing of pathogens, specially parasites is a key aspect

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of MCs-promoted innate immunity by histamine (St John and Abraham, 2013). Indeed, the presence of

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histamine in the gastric mucosa, as a regulatory molecule of acid gastric secretion, is a general feature in

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all vertebrates (Mulero et al., 2007). In fish GALT, the mechanistic process that occurs during a parasitic

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infection differs from that occurring in the mammalian type: while the expression of an analogous

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high-affinity immunoglobulin E (IgE)-like receptor (FcRI) has been reported, and possible Ig-binding to

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the Fc receptor, the cognate ligand IgE is not present (Da’as et al., 2011). Thus, in fish histamine release

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from MCs must be achieved by other means. In this regard, Mulero and colleagues reported that

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Perciform fish phagocytes are regulated by the release of histamine from MCs upon activation (Mulero et

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al., 2007). Subsequently, a study in which seabream was exposed to the parasite Enteromyxum leei

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through the anal route, revealed the proliferation of leukocytes with an increased histamine content in

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lymphohematopoietic organs and their recruitment into the intestines via blood circulation involving

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elements of innate and adaptive immunity (Estensoro et al., 2014). However, due the lack of homology

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among the full set of immune elements between mammals and fish, the mechanistic elements could not be

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fully detailed. Therefore, as in higher vertebrates histamine has been reported to stimulate GCs resulting

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in the secretion of mucus containing mucins mediated by histamine receptor 2 (H2R), we anticipate that a

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detailed assessment of gene expression and focused functional analyses would shed light on the

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mechanisms followed by histamine on the immune regulation in fish GALT.

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Mast cells

Among the wide repertoire of innate immune cells, MCs are critical players of the hematopoietic

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lineage that have evolutionary conserved functions in immunological homeostasis, disorders and

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pathogen surveillance (Goto et al., 2015; St John and Abraham, 2013). MCs have been reported in all

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classes of vertebrates, from fish to amphibians, reptiles, birds, marsupials, monotreme, and mammals 8

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(McMenamin and Polla, 2013). Current observations in several fish species except sharks clearly point to

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the crucial location in all the connective tissues of a cell type, namely MCs. , Among the connective

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tissue, the skin, gill filaments, brain and the intestinal submucosa layer MCs are included, suggesting that

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these cells play an active role in pathogen recognition or other signs of infection (Dezfuli et al., 2010;

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Mulero et al., 2007; Reite and Evensen, 2006). The close association of MCs with both epithelial and

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endothelial barriers strategically places them among the first cells to encounter pathogens, along with

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other immune cells on the front line of infection like macrophages (Kunder et al., 2011). Depending on

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the balance of activating stimuli perceived by MCs, they release a panel of inflammatory mediators with a

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degree of specialization for the type of pathogen detected (Fig. 1). Fish MCs have been noted to respond

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by migration and degranulation (Mulero et al., 2007), lending support to previous suppositions that MCs

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are involved in host defense mechanisms and are indispensable in fighting many infectious diseases

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(Reite and Evensen, 2006). MCs can respond to various pathogens through classical pattern recognition

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receptors like TLRs, NLRs, Rig-I family receptors, and others (Feng et al., 2007; St John and Abraham,

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2013). However, there is evidence that besides traditional PRRs, MCs use other molecules that directly

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detect pathogens, their associated products or DAMPs. Among them, GPRs, AHR, certain chemokines

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and cytokines, CD40 ligand or even the surface-activating receptor CD48 which induces bacterial uptake

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creating intracellular bacterial reservoirs, but without intracellular degradation (Akahoshi et al., 2011;

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Castellani et al., 2009; Enoksson et al., 2013; Shin and Abraham, 2001; Yang et al., 2015; Zhou et al.,

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2013). Their cytochemical characteristics and involvement in pathological conditions have convinced

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most investigators that fish MCs are analogous to mammalian ones (Dezfuli et al., 2010). However, to

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date, no definitive functional characterization of fish MCs has been published.

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Fish MCs constitute a heterogeneous cell population exemplified by their diverse morphology, granular content, sensitivity to fixatives, and response to drugs (Crivellato and Ribatti, 2010). Besides

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basic similarities among MCs, basophilic granular cells or acidophilic/eosinophilic granular cells, it is

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generally accepted that fish MCs are involved in the induction of inflammatory responses through their

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effect on vasodilatation, neutrophil attraction and macrophage activation (Powell et al., 1991; Vallejo and

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Ellis, 1989) (Fig. 2). Surprisingly, they have also the capacity to inhibit these responses when a situation

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warrants such action. Such behavior may serve for multiple purposes, like restoring homeostasis after

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pathogen clearance, preventing tissue damage due to prolonged inflammation, or perhaps facilitating

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wound repair. Several investigators have demonstrated how fish MCs release their content by

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degranulation (Ellis, 1985; Estensoro et al., 2014; Mulero et al., 2007; Powell et al., 1991). Granules of

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fish MCs were believed until few years ago to contain components common to their mammalian

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counterparts such as antimicrobial peptides, lytic enzymes or serotonin, but not histamine

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(Galindo-Villegas and Hosokawa, 2004). However, recently, using unequivocal antibodies and

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immunostaining techniques, fish MC granules were confirmed as containing histamine, although only

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those species belonging to the largest and most evolutionarily advanced order of teleosts, the Perciformes,

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a group containing Nile tilapia (Oreochromis niloticus), sea bass (Dicentrarchus labrax) and seabream

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(Sparus aurata) (Mulero et al., 2007; Salim et al., 2012). Furthermore, functional studies indicated that

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the professional phagocyte function in fish may be regulated by the release of histamine from MCs upon

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histamine receptor engagement in target cells. Interestingly, in addition to histamine the cytoplasmic

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granules of MCs and granulocytes in teleost also contain piscidins, a class of broad spectrum antibiotic

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peptides which are delivered to the bacteria upon phagocytosis (Corrales et al., 2010; Dezfuli et al.,

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2012a; Mulero et al., 2008a). Together, these reports clearly demonstrate that the granules in fish MCs

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and granulocytes are armed with strong preformed bactericidal elements to immediately kill extracellular

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and intracellular pathogens by degranulation (Fig. 1). Whatever the explanation, there was clear evidence

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that histamine in Perciform MCs is biologically active, acting on professional phagocytes through the

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regulation of the inflammatory response in different tissues including the gut. In mammalian MCs, many

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signaling mediators upstream of degranulation have been identified, suggesting that generation of Ca2+

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flux is a common requirement in the responding cell (Kalesnikoff and Galli, 2011). In fish, no similar

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pathway has been reported, but with the aid of recently developed tools important clues on possible

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therapeutic strategies and the evolutive relations between MCs and the host could be applied to improving

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the fish GALT immune status.

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Histamine: The new mediator in fish MCs granules.

In mammals, histamine exerts a range of effects on many physiological and pathological processes

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including, the regulation of gastrointestinal and circulatory functions, allergy, embryonic development,

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neurotransmission, brain functions, the secretion of pituitary hormones, wound healing, circulatory

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disease, mastocytosis and carcinogenesis (Kennedy et al., 2012; Rosignuolo et al., 2015; Smolinska et al.,

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2014; Yang et al., 2011). This biogenic amine can be produced by a wide variety of cell types including

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gastric enterochromaffin-like cells, histaminergic neurons, platelets, dendritic cells and T cells. But,

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without doubt MCs and basophils are the major source of the histamine stored to respond to

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immunological or environmental stimuli by degranulation (Fang and Xiang, 2015). Among the full

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vertebrate lineage, the systemic or local content of histamine is controversial. Until recently, it was

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believed that mammalian and avian MCs contained high histamine concentrations in their granules, while

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it was absent in fish and amphibian, and various amounts were present in reptilian (Reite, 1965). In the

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case of fish, biologically active histamine, which regulates inflammation by acting on granulocytes, has

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only been demonstrated in fish MCs of the Perciformes order (Mulero et al., 2007) (Fig. 1). As in all

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other taxa, the enzyme histidine decarboxylase (HDC) synthesizes histamine through the decarboxylation

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of the essential amino acid L-histidine (Martinel Lamas et al., 2015; Sundvik et al., 2011). In addition,

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certain bacteria can express HDC. In fish, this phenomenon is mostly attributed to flesh fermentation and

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is frequently related to fish poisoning (Bjornsdottir-Butler et al., 2015; Moon et al., 2013), an issue

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beyond the scope of this review. HDC expression and histamine release is influenced by cytokines

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including IL-1, IL-3, IL-12, IL-18, GM-CSF, MCSF and TNFa, and, in mammalian cells cultured in vitro

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by calcium ionophores (Ferstl et al., 2012; Jutel et al., 2009). As a key feature, histamine has been shown

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to strongly modulate the immune response by influencing most cells of the immune system and

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selectively recruiting them into tissue sites, affecting their maturation, activation, polarization, and

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effector functions and leading to an immediate APR (Fig. 2), and thereafter to chronic inflammatory

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reactions (Alcañiz et al., 2013; Novak et al., 2012; Rossbach et al., 2015). Within the mammalian

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gastrointestinal tract, histamine levels can be influenced by host allergic and inflammatory responses, the

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altered activity of degradative enzymes, dietary intake, and microbial processes (Smolinska et al., 2014).

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In fish GALT, recent investigations have generated much interest in the immune-regulatory mechanisms

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triggered by histamine; however, diverse experimental systems in mice have yielded conflicting data,

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indicating either pro- or anti-inflammatory effects, which seem to be dependent on the cells and type of

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histamine receptor expressed, as will be discussed in the next section (Beghdadi et al., 2008; Metz et al.,

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2011; Vukman et al., 2012).

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Receptors: Key mediators in the recognition of histamine.

In all vertebrates studied so far, histamine has been found to be consistently present along the

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gut-brain axis, which results from the interactions among intestinal mast cells, enteric neurons and

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visceral afferents (Buhner and Schemann, 2012). In the brain, histamine acts as a modulator of several

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neurotransmitters mainly by controlling feeding behavior in a complex fashion (Ishizuka and

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Yamatodani, 2012). Thus, like many neurotransmitters, changes in the intraneuronal levels of cyclic

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nucleotides are the initial biochemical event within the cell linked to receptor activation. In support of this

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notion, recent works have demonstrated the differential involvement of histamine in the appetite, food

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anticipatory responses, and in food consumption, indicating the tight link between the brain and the

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digestive system (Linster and Fontanini, 2014; Provensi et al., 2015; Zendehdel et al., 2015).

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In teleost fish, evidence of a gut-brain-axis has been recently demonstrated by the action of

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glucagon-like peptide-1 (GLP-1) on glucose and energy homeostasis mediated by vagal and splenic

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afferents (Polakof et al., 2011). Unfortunately, this finding is beyond the focus of the present review as it

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was conducted in rainbow trout which has MCs, but their granules are devoid of histamine (Mulero et al.,

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2007). However, in the yellowtail (Seriola quinqueradiata), a perciform species, the presence of several

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modifiers of acid secretion which are mediated by specific receptors for ghrelin, cholecystokinin or

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GLP-1 located in the gut have been identified (Furutani et al., 2013; Murashita et al., 2007; Schubert,

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2015). Therefore, we anticipate that in perciforms a similar gut-brain axis interaction mediated by

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histamine and its receptors may be possible, which, if proven to be the case, would be of interest as a new 11

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immunological and nutritional management tool in the aquaculture industry. The regulatory nature of histamine in immunology is fully dependent on its binding to a specific

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subtype of histamine receptor, which in mammals are represented by four members (H1R, H2R, H3R and

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H4R) belonging to the rhodopsin-like family of G protein-coupled receptors (GPCR). These receptors are

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differentially expressed in various histamine responsive tissues and cells, and suggest a critical role of

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histamine in immunomodulation (Jutel et al., 2006). HR1is expressed by a broad range of cells and its

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expression can be up-regulated by IL-3, IL-4 and histamine (Gschwandtner et al., 2013). Activation of

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H1R is associated with an immediate-type hypersensitivity response, such as redness, itching and

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swelling. Similar to H1R, H2R is expressed in a variety of tissues and cells, including the gastric parietal

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cell and smooth muscle. H2R can modulate a range of immune system activities, such as MCs

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degranulation, cytokine production, T-cell polarization and the release of ROS produced by NADPH

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oxidase (Morel et al., 1991; Vallejo and Ellis, 1989). Canonically, the H2R couples to Gs-proteins, which

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in turn, leads to activation of cAMP (Werner et al., 2014). However, in specific cell systems, the H2R

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couples non-canonically to Gq-proteins, resulting in phospholipase C (PLC) activation and increases in

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intracellular calcium concentration ([Ca2+]) (Seifert et al., 1992). Therefore, if histamine regulates ROS

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activity in acidophilic granulocytes of seabream, and developmental immunity is induced by osmotic

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stress following a TRPV4/ Ca2+/TAK1/NF-κB signaling pathway, mediated by intracellular Ca2+ and PLC

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in zebrafish (Galindo-Villegas et al., 2016), a possible relationship between H2R, the above described

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elements and key effectors in the GALT of Perciform fish is worth investigating. H3R is a pre-synaptic

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auto receptor in the peripheral and central nervous system and has been related to the homeostatic

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regulation of energy and inflammation (Kyriakidis et al., 2014). These findings have been supported

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using H3R-KO mice, which were seen to suffer an increased severity of neuroinflammatory diseases

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associated with the enhanced expression of adhesion molecules, chemokines and peripheral T-cells. H4R

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in mammals shares some properties with H3R and is essential as a mediator of the effects of histamine on

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iNKT (Rossbach et al., 2015). However, in fish H3R seldom has been reported and H4R has not yet been

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described, although the following experiments will illustrate the diversity of histamine receptors in fish.

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Using H1R and H2R agonists and the potentiator compound 48/80, changes in melanophore size were

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determined (Salim and Ali, 2011). In Oreochromis mossambicus both receptors, H1R and HR2, mediate

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melanophore aggregation and dispersion respectively (Salim et al., 2012). In a different study, using sea

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bream intestinal smooth muscle the impact of histamine on the cardiovascular system was assessed

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(Mulero et al., 2007). Histamine, H2R agonist and compound 48/80, but not H1R, caused a strong

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contraction of the intestinal smooth muscle and constriction of branchial blood vessels. To demonstrate

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specificity all these effects were reversed with the H2R antagonist ranitidine, suggesting that both,

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histamine and H2R are essential players in the fish intestine. Mechanistically, the same authors showed

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that histamine is important in the regulation of fish professional phagocyte activity. Moreover, histamine

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and the H1R agonist pyridilethylamine were both found to strongly inhibit the phagocyte respiratory burst

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activity primed by bacterial DNA, whereas an H2R agonist had the opposite effect; that is, it further

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increased this activity. Hence, these results suggest that histamine regulates fish phagocyte functions in a

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complex manner through the engagement of different receptors, as has been shown in murine

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macrophages, where histamine acting on H1R and H2R restricts the growth of Mycobacterium bovis

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bacillus via the production of interleukin-18 (Megyeri et al., 2006). In contrast, in an Escherichia coli

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infectious peritonitis model, histamine acting on H1 and H2 receptors impaired neutrophil recruitment,

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which delayed the elimination of bacteria (Hori et al., 2002). Whatever the outcome, seabream intestinal

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MCs secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect

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their maturation, activation, polarization and effector functions leading to tolerogenic or

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pro-inflammatory responses.

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6.

Conclusions

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Throughout the vertebrate lineage, histamine contained in MCs has a key role in many physiological processes. Several constraints, ranging from the complication of differentiating the different maturation

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stages of MCs to a lack of tools to conduct research using perciform fish models, slow down advances in

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this research field. However, clarifying the full set of signaling pathways related to the inflammatory

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processes triggered by this biogenic amine in the fish GALT is a particularly attractive goal for both

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scientific and commercial reasons.

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Acknowledgements

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To the European Commission for supporting VM and JG-V under the 7th Framework Program

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for Research and Technological Development (FP7) of the European Union through the Grant Agreement

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311993 TARGETFISH.

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Figure Legends

380 Fig. 1 Mast cells production, migration and activation in Perciformes. Originated in hematopoietic

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tissue, the head-kidney MC migrate through the blood stream to finally settle down in specific mucosal

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tissue, like the gut where they acquire their definite morphology. Upon detection and depending on the

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balance of activating stimuli MC response by typical degranulation releasing preformed mediators,

385

including histamine. Once depleted, MC can replenish their granules with newly transcribed mediators,

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live for long periods and even proliferate.

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Fig 2 Simplified representation of the roles played by histamine released by MC in the fish GALT.

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Several molecules have the capacity to activate MCs and release immediately pre-stored mediators

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including histamine. Among the effector capacity of histamine are the vasodilatation, increased vascular

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flux and permeability, increased smooth muscle contractions, and release of cytokines and chemokines by

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different several cellular types in the lamina propia containing the fish GALT. Epithelial cells have the

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capacity of phagocyte antigen or to recognize PAMPs by classical PRRs. Antigen is transferred to active

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macrophages which would latter present it to polarized lymphocytes. Directly by parasites or through a

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downstream signaling, pro-inflammatory mediators activate MC for degranulation. All cells which

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recognize histamine is trough histamine receptors, like H2R. MC also display histamine receptors and

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could be autoregulated. Goblet cells upon recognition of histamine increase the mucine production and

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therefore the mucus hydrogel layer to avoid pathogens attachment to the epithelial wall. Activated

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granulocytes are negatively regulated by histamine impairing their capacities to produce mediators or

400

effector molecules. Interestingly, protection against intestinal helminthic infection, if ILC2 are present

401

could be acting through a negative-feedback regulation of IL-5, IL-9 and IL-13 in response to IL-25 and

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IL-33 which in turn promotes mucus over production by goblet cells, expansion and recruitment of

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mucosal MC following histamine degranulation which results in hypermotility and contraction of smooth

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muscle and blood vessels. Solid lines represent effector mechanisms and dotted lines represent the effect

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triggered by histamine of MC.

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References

410

Abraham, S.N., St John, A.L., 2010. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 10,

412

440–452. doi:10.1038/nri2782 Akahoshi, M., Song, C.H., Piliponsky, A.M., Metz, M., Guzzetta, A., Abrink, M., Schlenner, S.M.,

RI PT

411

413

Feyerabend, T.B., Rodewald, H.R., Pejler, G., Tsai, M., Galli, S.J., 2011. Mast cell chymase

414

reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal

415

polypeptide in mice. J Clin Invest 121, 4180–4191. doi:10.1172/JCI46139

Alcañiz, L., Vega, A., Chacón, P., El Bekay, R., Ventura, I., Aroca, R., Blanca, M., Bergstralh, D.T.,

SC

416

Monteseirin, J., 2013. Histamine production by human neutrophils. FASEB J 27, 2902–2910.

418

doi:10.1096/fj.12-223867

419

M AN U

417

Baccari, G.C., Pinelli, C., Santillo, A., Minucci, S., Rastogi, R.K., 2011. Mast cells in nonmammalian

420

vertebrates: an overview. Int Rev Cell Mol Biol 290, 1–53.

421

doi:10.1016/B978-0-12-386037-8.00006-5

422

Balla, K.M., Lugo-Villarino, G., Spitsbergen, J.M., Stachura, D.L., Hu, Y., Bañuelos, K., Romo-Fewell, O., Aroian, R.V., Traver, D., 2010. Eosinophils in the zebrafish: prospective isolation,

424

characterization, and eosinophilia induction by helminth determinants. Blood 116, 3944–3954.

425

doi:10.1182/blood-2010-03-267419

TE D

423

Ballesteros, N.A., Castro, R., Abos, B., Rodríguez Saint-Jean, S.S., Pérez-Prieto, S.I., Tafalla, C.,

427

2013. The Pyloric Caeca Area Is a Major Site for IgM+ and IgT+ B Cell Recruitment in

428

Response to Oral Vaccination in Rainbow Trout. PLoS ONE 8(6): e66118.

430 431 432 433 434

AC C

429

EP

426

doi:10.1371/journal.pone.0066118

Beck, G., Ellis, T.W., Habicht, G.S., Schluter, S.F., Marchalonis, J.J., 2002. Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule. Dev Comp Immunol 26, 11–26. Beghdadi, W., Porcherie, A., Schneider, B.S., Dubayle, D., Peronet, R., Huerre, M., Watanabe, T., Ohtsu, H., Louis, J., Mécheri, S., 2008. Inhibition of histamine-mediated signaling confers significant

15

ACCEPTED MANUSCRIPT

435

protection against severe malaria in mouse models of disease. J Exp Med 205, 395–408.

436

doi:10.1084/jem.20071548

437

Bjornsdottir-Butler, K., Bowers, J.C., Benner, R.A., 2015. Prevalence and Characterization of High Histamine-Producing Bacteria in Gulf of Mexico Fish Species. J Food Prot 78, 1335–1342.

439

doi:10.4315/0362-028X.JFP-15-012

441 442

Buhner, S., Schemann, M., 2012. Mast cell-nerve axis with a focus on the human gut. Biochim Biophys Acta 1822, 85–92. doi:10.1016/j.bbadis.2011.06.004

SC

440

RI PT

438

Castellani, M.L., Kempuraj, D., Salini, V., Vecchiet, J., Tete, S., Ciampoli, C., Conti, F., Cerulli, G., Caraffa, A., Antinolfi, P., Theoharides, T.C., De Amicis, D., Perrella, A., Cuccurullo, C.,

444

Boscolo, P., Shaik, Y., 2009. The latest interleukin: IL-33 the novel IL-1-family member is a

445

potent mast cell activator. J Biol Regul Homeost Agents 23, 11–14.

446 447 448

M AN U

443

Corfield, A.P., 2015. Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta 1850, 236–252. doi:10.1016/j.bbagen.2014.05.003

Corrales, J., Mulero, I., Mulero, V., Noga, E.J., 2010. Detection of antimicrobial peptides related to piscidin 4 in important aquacultured fish. Dev Comp Immunol 34, 331–343.

450

doi:10.1016/j.dci.2009.11.004

453 454 455 456 457

347–360. doi:10.1111/j.1469-185X.2009.00105.x

EP

452

Crivellato, E., Ribatti, D., 2010. The mast cell: an evolutionary perspective. Biol Rev Camb Philos Soc 85,

Crivellato, E., Travan, L., Ribatti, D., 2015. The phylogenetic profile of mast cells. Methods Mol Biol 1220, 11–27. doi:10.1007/978-1-4939-1568-2_2

AC C

451

TE D

449

Csaba, G., 2015. Mast cell, the peculiar member of the immune system: A homeostatic aspect. Acta Microbiol Immunol Hung 62, 207–231. doi:10.1556/030.62.2015.3.1

Da’as, S., Teh, E.M., Dobson, J.T., Nasrallah, G.K., McBride, E.R., Wang, H., Neuberg, D.S., Marshall,

458

J.S., Lin, T.J., Berman, J.N., 2011. Zebrafish mast cells possess an FcɛRI-like receptor and

459

participate in innate and adaptive immune responses. Dev Comp Immunol 35, 125–134.

460

doi:10.1016/j.dci.2010.09.001 16

ACCEPTED MANUSCRIPT

461

Dezfuli, B.S., Castaldelli, G., Bo, T., Lorenzoni, M., Giari, L., 2011a. Intestinal immune response of

462

Silurus glanis and Barbus barbus naturally infected with Pomphorhynchus laevis

463

(Acanthocephala). Parasite Immunol 33, 116–123. doi:10.1111/j.1365-3024.2010.01266.x

465 466

Dezfuli, B.S., Giari, L., 2008. Mast cells in the gills and intestines of naturally infected fish: evidence of migration and degranulation. J Fish Dis 31, 845–852.

RI PT

464

Dezfuli, B.S., Giari, L., Squerzanti, S., Lui, A., Lorenzoni, M., Sakalli, S., Shinn, A.P., 2011b. Histological damage and inflammatory response elicited by Monobothrium wageneri (Cestoda) in the

468

intestine of Tinca tinca (Cyprinidae). Parasit Vectors 4, 225. doi:10.1186/1756-3305-4-225

469

SC

467

Dezfuli, B.S., Lui, A., Giari, L., Castaldelli, G., Mulero, V., Noga, E.J., 2012a. Infiltration and activation of acidophilic granulocytes in skin lesions of gilthead seabream, Sparus aurata, naturally

471

infected with lymphocystis disease virus. Dev Comp Immunol 36, 174–182.

472

doi:10.1016/j.dci.2011.06.017

473

M AN U

470

Dezfuli, B.S., Lui, A., Giari, L., Castaldelli, G., Shinn, A.P., Lorenzoni, M., 2012b. Innate immune defence mechanisms of tench, Tinca tinca (L.), naturally infected with the tapeworm Monobothrium

475

wageneri. Parasite Immunol 34, 511–519. doi:10.1111/j.1365-3024.2012.01373.x

476

Dezfuli, B.S., Manera, M., Giari, L., DePasquale, J.A., Bosi, G., 2015a. Occurrence of immune cells in

477

the intestinal wall of Squalius cephalus infected with Pomphorhynchus laevis. Fish Shellfish

478

Immunol 47, 556–564. doi:10.1016/j.fsi.2015.09.043

481 482 483 484 485 486

EP

480

Dezfuli, B.S., Manera, M., Lorenzoni, M., Pironi, F., Shinn, A.P., Giari, L., 2015b. Histopathology and the inflammatory response of European perch, Perca fluviatilis muscle infected with

AC C

479

TE D

474

Eustrongylides sp. (Nematoda). Parasit Vectors 8, 227. doi:10.1186/s13071-015-0838-x

Dezfuli, B.S., Pironi, F., Giari, L., Noga, E.J., 2010. Immunocytochemical localization of piscidin in mast cells of infected seabass gill. Fish Shellfish Immunol 28, 476–482. doi:10.1016/j.fsi.2009.12.012 Dobson, J.T., Seibert, J., Teh EM, Da'as S., Fraser R.B., Paw, B.H., Lin, T.J., Berman, J.N., 2008. Carboxypeptidase A5 identifies a novel mast cell lineage in the zebrafish providing new insight

17

ACCEPTED MANUSCRIPT

487

into mast cell fate determination. Blood. 2008 Oct 1;112(7):2969-72. doi:

488

10.1182/blood-2008-03-145011.

489

Dorin, D., Sire, M.F., Vernier, J.M., 1993. Endocytosis and intracellular degradation of heterologous protein by eosinophilic granulocytes isolated from rainbow trout (Oncorhynchus mykiss)

491

posterior intestine. Biol Cell 79, 219–224.

493 494

Ellis, A.E., 1985. Eosinophilic granular cells (EGC) and histamine responses to Aeromonas salmonicida toxins in rainbow trout. Dev Comp Immunol 9, 251–260.

SC

492

RI PT

490

Enoksson, M., Möller-Westerberg, C., Wicher, G., Fallon, P.G., Forsberg-Nilsson, K., Lunderius-Andersson, C., Nilsson, G., 2013. Intraperitoneal influx of neutrophils in response

496

to IL-33 is mast cell-dependent. Blood 121, 530–536. doi:10.1182/blood-2012-05-434209

497

Estensoro, I., Mulero, I., Redondo, M.J., Alvarez-Pellitero, P., Mulero, V., Sitjà-Bobadilla, A., 2014.

M AN U

495

498

Modulation of leukocytic populations of gilthead sea bream (Sparus aurata) by the intestinal

499

parasite Enteromyxum leei (Myxozoa: Myxosporea). Parasitology 141, 425–440.

500

doi:10.1017/S0031182013001789

502 503

Fang, Y., Xiang, Z., 2015. Roles and relevance of mast cells in infection and vaccination. J Biomed Res

TE D

501

30. doi:10.7555/JBR.30.20150038

Feng, B.S., He, S.H., Zheng, P.Y., Wu, L., Yang, P.C., 2007. Mast cells play a crucial role in Staphylococcus aureus peptidoglycan-induced diarrhea. Am J Pathol 171, 537–547.

505

doi:10.2353/ajpath.2007.061274

507 508 509

Ferstl, R., Akdis, C.A., O’Mahony, L., 2012. Histamine regulation of innate and adaptive immunity. Front

AC C

506

EP

504

Biosci (Landmark Ed) 17, 40–53.

Furutani, T., Masumoto, T., Fukada, H., 2013. Molecular cloning and tissue distribution of cholecystokinin-1 receptor (CCK-1R) in yellowtail Seriola quinqueradiata and its response to

510

feeding and in vitro CCK treatment. Gen Comp Endocrinol 186, 1–8.

511

doi:10.1016/j.ygcen.2013.02.003

512 513

Galindo-Villegas, J., García-Moreno, D., de Oliveira, S., Meseguer, J., Mulero, V., 2012. Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during 18

ACCEPTED MANUSCRIPT

514

zebrafish development. Proc Natl Acad Sci U S A 109, E2605–E2614.

515

doi:10.1073/pnas.1209920109

517

Galindo-Villegas, J., Hosokawa,H., 2004. Immunostimulants: towards temporary prevention of diseases in marine fish. Trends in Aqua. Nut. VII:279-319

RI PT

516

Galindo-Villega, J., Montalban-Arques, A., Liarte, S., de Oliveira, S., Pardo-Pastor, C., Rubio-Moscardo,

519

F., Meseguer, J., Valverde, M. A., Mulero, V., 2016. TRPV4-Mediated Detection of Hyposmotic

520

Stress by Skin Keratinocytes Activates Developmental Immunity. J Immunol 196: [Epub ahead

521

of print] doi/10.4049/jimmunol.1501729

522

SC

518

Galindo-Villegas, J., Mulero, I., García-Alcazar, A., Muñoz, I., Peñalver-Mellado, M., Streitenberger, S., Scapigliati, G., Meseguer, J., Mulero, V., 2013. Recombinant TNFα as oral vaccine adjuvant

524

protects European sea bass against vibriosis: insights into the role of the CCL25/CCR9 axis.

525

Fish Shellfish Immunol 35, 1260–1271. doi:10.1016/j.fsi.2013.07.046

526

M AN U

523

Georgopoulou, U., Vernier, J.M., 1986. Local immunological response in the posterior intestinal segment of the rainbow trout after oral administration of macromolecules. Dev Comp Immunol 10,

528

529–537.

531 532 533 534 535 536

doi:10.1016/j.smim.2015.05.003

Goto, Y., Kurashima, Y., Kiyono, H., 2015. Roles of the gut mucosal immune system in symbiosis and

EP

530

Gilroy, D., De Maeyer, R., 2015. New insights into the resolution of inflammation. Semin Immunol.

immunity. Rinsho Ketsueki 56, 2205–2212. doi:10.11406/rinketsu.56.2205 Gschwandtner, M., Mildner, M., Mlitz, V., Gruber, F., Eckhart, L., Werfel, T., Gutzmer, R., Elias, P.M.,

AC C

529

TE D

527

Tschachler, E., 2013. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy 68, 37–47. doi:10.1111/all.12051

Hellberg, H., Bjerkås, I., Vågnes, O.B., Noga, E.J., 2013. Mast cells in common wolffish anarhichas lupus

537

l.: ontogeny, distribution and association with lymphatic vessels. Fish Shellfish Immunol.

538

doi:10.1016/j.fsi.2013.08.031

19

ACCEPTED MANUSCRIPT

539

Hori, Y., Nihei, Y., Kurokawa, Y., Kuramasu, A., Makabe-Kobayashi, Y., Terui, T., Doi, H., Satomi, S.,

540

Sakurai, E., Nagy, A., Watanabe, T., Ohtsu, H., 2002. Accelerated clearance of Escherichia

541

coli in experimental peritonitis of histamine-deficient mice. J Immunol 169, 1978–1983.

545 546 547

RI PT

544

21–27.

Ishizuka, T., Yamatodani, A., 2012. Integrative role of the histaminergic system in feeding and taste perception. Front Syst Neurosci 6, 44. doi:10.3389/fnsys.2012.00044

SC

543

Huang, J.F., Thurmond, R.L., 2008. The new biology of histamine receptors. Curr Allergy Asthma Rep 8,

Jevtov, I., Samuelsson, T., Yao, G., Amsterdam, A., Ribbeck, K., 2014. Zebrafish as a model to study live mucus physiology. Sci Rep 4, 6653. doi:10.1038/srep06653

M AN U

542

548

Johansson, M.E., Larsson, J.M., Hansson, G.C., 2011. The two mucus layers of colon are organized by

549

the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc

550

Natl Acad Sci U S A 108 Suppl 1, 4659–4665. doi:10.1073/pnas.1006451107

551

Jutel, M., Akdis, M., Akdis, C.A., 2009. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 39, 1786–1800. doi:10.1111/j.1365-2222.2009.03374.x

553

Jutel, M., Blaser, K., Akdis, C.A., 2006. Histamine receptors in immune regulation and allergen-specific

TE D

552

immunotherapy. Immunol Allergy Clin North Am 26, 245–59, vii.

555

doi:10.1016/j.iac.2006.02.006

557

Kalesnikoff, J., Galli, S.J., 2011. Antiinflammatory and immunosuppressive functions of mast cells. Methods Mol Biol 677, 207–220. doi:10.1007/978-1-60761-869-0_15

AC C

556

EP

554

558

Kennedy, L., Hodges, K., Meng, F., Alpini, G., Francis, H., 2012. Histamine and histamine receptor

559

regulation of gastrointestinal cancers. Transl Gastrointest Cancer 1, 215–227.

560 561 562 563

Kim, J.J., Khan, W.I., 2013. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens 2, 55–70. doi:10.3390/pathogens2010055 Kunder, C.A., St John, A.L., Abraham, S.N., 2011. Mast cell modulation of the vascular and lymphatic endothelium. Blood 118, 5383–5393. doi:10.1182/blood-2011-07-358432

20

ACCEPTED MANUSCRIPT

564

Kyriakidis, K., Zampeli, E., Palaiologou, M., Tiniakos, D., Tiligada, E., 2014. Histamine H3 and H 4

565

Receptor Ligands Modify Vascular Histamine Levels in Normal and Arthritic Large Blood

566

Vessels In Vivo. Inflammation. doi:10.1007/s10753-014-0057-1 Lauriano, E.R., Calò, M., Silvestri, G., Zaccone, D., Pergolizzi, S., Lo Cascio, P., 2012. Mast cells in the

RI PT

567 568

intestine and gills of the sea bream, Sparus aurata, exposed to a polychlorinated biphenyl,

569

PCB 126. Acta Histochem 114, 166–171. doi:10.1016/j.acthis.2011.04.004

573 574 575 576 577 578

SC

572

78–89. doi:10.1016/j.fsi.2014.04.015

Licona-Limón, P., Kim, L.K., Palm, N.W., Flavell, R.A., 2013. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14, 536–542. doi:10.1038/ni.2617

M AN U

571

Lazado, C.C., Caipang, C.M., 2014. Mucosal immunity and probiotics in fish. Fish Shellfish Immunol 39,

Linster, C., Fontanini, A., 2014. Functional neuromodulation of chemosensation in vertebrates. Curr Opin Neurobiol 29, 82–87. doi:10.1016/j.conb.2014.05.010

Løkka, G., Austbø, L., Falk, K., Bjerkås, I., Koppang, E.O., 2013. Intestinal morphology of the wild Atlantic salmon (Salmo salar). J Morphol. 2013 Aug;274(8):859-76. doi: 10.1002/jmor.20142.

TE D

570

Magrone, T., Jirillo, E., 2013. The interplay between the gut immune system and microbiota in health and disease: nutraceutical intervention for restoring intestinal homeostasis. Curr Pharm Des 19,

580

1329–1342.

582 583 584 585 586 587 588

Maizels, R.M., Hewitson, J.P., Smith, K.A., 2012. Susceptibility and immunity to helminth parasites. Curr Opin Immunol 24, 459–466. doi:10.1016/j.coi.2012.06.003

AC C

581

EP

579

Manera, M., Giammarino, A., Borreca, C., Giari, L., Dezfuli, B.S., 2011. Degranulation of mast cells due to compound 48/80 induces concentration-dependent intestinal contraction in rainbow trout (Oncorhynchus mykiss Walbaum) ex vivo. J Exp Zool A Ecol Genet Physiol 315, 447–457. doi:10.1002/jez.692

Martinel Lamas, D.J., Rivera, E.S., Medina, V.A., 2015. Histamine H4 receptor: insights into a potential therapeutic target in breast cancer. Front Biosci (Schol Ed) 7, 1–9.

21

ACCEPTED MANUSCRIPT

589

Matsuyama, T., Iida, T., 1999. Degranulation of eosinophilic granular cells with possible involvement in

590

neutrophil migration to site of inflammation in tilapia. Dev Comp Immunol 23, 451–457.

591

McMenamin, P.G., Polla, E., 2013. Mast cells are present in the choroid of the normal eye in most

593

vertebrate classes. Vet Ophthalmol. doi:10.1111/vop.12035

RI PT

592

Megyeri, K., Buzás, K., Miczák, A., Buzás, E., Kovács, L., Seprényi, G., Falus, A., Mándi, Y., 2006. The role of histamine in the intracellular survival of Mycobacterium bovis BCG. Microbes Infect 8,

595

1035–1044. doi:10.1016/j.micinf.2005.10.022

596

SC

594

Metz, M., Doyle, E., Bindslev-Jensen, C., Watanabe, T., Zuberbier, T., Maurer, M., 2011. Effects of antihistamines on innate immune responses to severe bacterial infection in mice. Int Arch

598

Allergy Immunol 155, 355–360. doi:10.1159/000321614

599

M AN U

597

Montalban-Arques, A., De Schryver, P., Bossier, P., Gorkiewicz, G., Mulero, V., Gatlin, D.M.,

600

Galindo-Villegas, J., 2015. Selective Manipulation of the Gut Microbiota Improves Immune

601

Status in Vertebrates. Front Immunol 6, 512. doi:10.3389/fimmu.2015.00512

602

Moon, J.S., Kim, S.Y., Cho, K.J., Yang, S.J., Yoon, G.M., Eom, H.J., Han, N.S., 2013. Isolation and characterization of histamine-producing bacteria from fermented fish products. J Microbiol 51,

604

881–885. doi:10.1007/s12275-013-3333-0

607 608 609

Physiological, molecular and pathological aspects. Eur J Biochem 201, 523–546.

EP

606

Morel, F., Doussiere, J., Vignais, P.V., 1991. The superoxide-generating oxidase of phagocytic cells.

Morita,H., Sugita, K., Ferstl,R., Frei, R., Kubo, T., Van De Veen, W., Wawrzyniak, M., Wirz,O., Rückert, B., O'Mahony, L., Akdis,M., Akdis, C., 2015. The effects of histamine on type 2 innate lymphoid

AC C

605

TE D

603

cells. EAACI Online Library. Morita H. Jun 6, 2015; 103852

610

Mulero, I., Noga, E.J., Meseguer, J., García-Ayala, A., Mulero, V., 2008a. The antimicrobial peptides

611

piscidins are stored in the granules of professional phagocytic granulocytes of fish and are

612

delivered to the bacteria-containing phagosome upon phagocytosis. Dev Comp Immunol 32,

613

1531–1538. doi:10.1016/j.dci.2008.05.015

614 615

Mulero, I., Sepulcre, M.P., Roca, F.J., Meseguer, J., García-Ayala, A., Mulero, V., 2008b. Characterization of macrophages from the bony fish gilthead seabream using an antibody 22

ACCEPTED MANUSCRIPT

616

against the macrophage colony-stimulating factor receptor. Dev Comp Immunol 32,

617

1151–1159. doi:10.1016/j.dci.2008.03.005

618

Mulero, I., Sepulcre, M.P., Meseguer, J., García-Ayala, A., Mulero, V., 2007. Histamine is stored in mast cells of most evolutionarily advanced fish and regulates the fish inflammatory response. Proc

620

Natl Acad Sci U S A 104, 19434–19439. doi:10.1073/pnas.0704535104

621

RI PT

619

Murashita, K., Fukada, H., Hosokawa, H., Masumoto, T., 2007. Changes in cholecystokinin and peptide Y gene expression with feeding in yellowtail (Seriola quinqueradiata): relation to pancreatic

623

exocrine regulation. Comp Biochem Physiol B, Biochem Mol Biol 146, 318–325.

624

doi:10.1016/j.cbpb.2006.11.009

Murashita, K., Fukada, H., Rønnestad, I., Kurokawa, T., Masumoto, T., 2008. Nutrient control of release

M AN U

625

SC

622

626

of pancreatic enzymes in yellowtail (Seriola quinqueradiata): Involvement of CCK and PY in

627

the regulatory loop. Comparative Biochemistry and Physiology, Part A 150 (2008) 438–443.

628

doi:10.1016/j.cbpa.2008.05.003

629 630

Murray, H.M., Gallant, J.W., Douglas, S.E., 2003. Cellular localization of pleurocidin gene expression and synthesis in winter flounder gill using immunohistochemistry and in situ hybridization.

632

Cell Tissue Res 312, 197–202. doi:10.1007/s00441-003-0723-3

633

TE D

631

Novak, N., Mete, N., Bussmann, C., Maintz, L., Bieber, T., Akdis, M., Zumkehr, J., Jutel, M., Akdis, C., 2012. Early suppression of basophil activation during allergen-specific immunotherapy by

635

histamine receptor 2. J Allergy Clin Immunol 130, 1153–1158.e2.

636

doi:10.1016/j.jaci.2012.04.039

638 639 640 641

AC C

637

EP

634

Oskeritzian, C.A., 2012. Mast Cells and Wound Healing. Adv Wound Care (New Rochelle) 1, 23–28. doi:10.1089/wound.2011.0357

Parra, D., Reyes-Lopez, F.E., Tort, L., 2015. Mucosal Immunity and B Cells in Teleosts: Effect of Vaccination and Stress. Front Immunol 6, 354. doi:10.3389/fimmu.2015.00354 Pelaseyed, T., Bergström, J.H., Gustafsson, J.K., Ermund, A., Birchenough, G.M., Schütte, A., van der

642

Post, S., Svensson, F., Rodríguez-Piñeiro, A.M., Nyström, E.E., Wising, C., Johansson, M.E.,

643

Hansson, G.C., 2014. The mucus and mucins of the goblet cells and enterocytes provide the 23

ACCEPTED MANUSCRIPT

644

first defense line of the gastrointestinal tract and interact with the immune system. Immunol

645

Rev 260, 8–20. doi:10.1111/imr.12182

646

Pérez, T., Balcázar, J.L., Ruiz-Zarzuela, I., Halaihel, N., Vendrell, D., de Blas, I., Múzquiz, J.L., 2010. Host-microbiota interactions within the fish intestinal ecosystem. Mucosal Immunol 3,

648

355–360. doi:10.1038/mi.2010.12

RI PT

647

Pérez-Sánchez, J., Estensoro, I., Redondo, M.J., Calduch-Giner, J.A., Kaushik, S., Sitjà-Bobadilla, A.,

650

2013. Mucins as diagnostic and prognostic biomarkers in a fish-parasite model:

651

transcriptional and functional analysis. PLoS ONE 8, e65457.

652

doi:10.1371/journal.pone.0065457

Picchietti, S., Fausto, A.M., Randelli, E., Carnevali, O., Taddei, A.R., Buonocore, F., Scapigliati, G.,

M AN U

653

SC

649

654

Abelli, L., 2009. Early treatment with Lactobacillus delbrueckii strain induces an increase in

655

intestinal T-cells and granulocytes and modulates immune-related genes of larval

656

Dicentrarchus labrax (L.). Fish Shellfish Immunol 26, 368–376. doi:10.1016/j.fsi.2008.10.008

657

Polakof, S., Míguez, J.M., Soengas, J.L., 2011. Evidence for a gut-brain axis used by glucagon-like peptide-1 to elicit hyperglycaemia in fish. J Neuroendocrinol 23, 508–518.

659

doi:10.1111/j.1365-2826.2011.02137.x

660

TE D

658

Powell, M.D., Wright, G.M., Burka, J.F., 1991. Degranulation of eosinophilic granule cells induced by capsaicin and substance P in the intestine of the rainbow trout (Oncorhynchus mykiss

662

Walbaum). Cell Tissue Res 266, 469–474.

664 665 666 667 668 669

Provensi, G., Blandina, P., Passani, M.B., 2015. The histaminergic system as a target for the prevention

AC C

663

EP

661

of obesity and metabolic syndrome. Neuropharmacology. doi:10.1016/j.neuropharm.2015.07.002

Reber, L.L., Sibilano, R., Mukai, K., Galli, S.J., 2015. Potential effector and immunoregulatory functions of mast cells in mucosal immunity. Mucosal Immunol. doi:10.1038/mi.2014.131 Reite, O.B., 1965. A phylogenetical approach to the functional significance of tissue mast cell histamine. Nature 206, 1334–1336.

24

ACCEPTED MANUSCRIPT

670 671

Reite, O.B., 1998. Mast cells/eosinophilic granule cells of teleostean fish: a review focusing on staining properties and functional responses. Fish Shellfish Immunol 8, 489-513. Reite, O.B., 2005. The rodlet cells of teleostean fish: their potential role in host defence in relation to the

673

role of mast cells/eosinophilic granule cells. Fish Shellfish Immunol 19, 253–267.

674

doi:10.1016/j.fsi.2005.01.002

675

Reite, O.B., Evensen, O., 2006. Inflammatory cells of teleostean fish: a review focusing on mast

676

cells/eosinophilic granule cells and rodlet cells. Fish Shellfish Immunol 20, 192–208.

677

doi:10.1016/j.fsi.2005.01.012

SC

678

RI PT

672

Rocha, J.S., Chiarini-Garcia, H., 2007. Mast cell heterogeneity between two different species of Hoplias sp. (Characiformes: Erythrinidae): response to fixatives, anatomical distribution,

680

histochemical contents and ultrastructural features. Fish Shellfish Immunol 22, 218–229.

681

doi:10.1016/j.fsi.2006.05.002

685 686 687 688 689

Rombout, J.H., Abelli, L., Picchietti, S., Scapigliati, G., Kiron, V., 2011. Teleost intestinal immunology.

TE D

684

the mast cell lineage. Science 271, 818–822.

Fish Shellfish Immunol 31, 616–626. doi:10.1016/j.fsi.2010.09.001 Rombout, J.H., Taverne, N., van de Kamp, M., Taverne-Thiele, A.J., 1993. Differences in mucus and serum immunoglobulin of carp (Cyprinus carpio L.). Dev Comp Immunol 17, 309–317.

EP

683

Rodewald, H.R., Dessing, M., Dvorak, A.M., Galli, S.J., 1996. Identification of a committed precursor for

Rombout, J.H., Yang, G., Kiron, V., 2014. Adaptive immune responses at mucosal surfaces of teleost fish. Fish Shellfish Immunol 40, 634–643. doi:10.1016/j.fsi.2014.08.020

AC C

682

M AN U

679

690

Rosignuolo, M., Muscianese, M., Pranteda, G., 2015. Systemic mastocytosis presenting with

691

gastrointestinal, bone and skin involvement. J Ultrasound 18, 287–292.

692 693

doi:10.1007/s40477-014-0090-9

Rossbach, K., Schaper, K., Kloth, C., Gutzmer, R., Werfel, T., Kietzmann, M., Bäumer, W., 2015.

694

Histamine H4 receptor knockout mice display reduced inflammation in a chronic model of

695

atopic dermatitis. Allergy. doi:10.1111/all.12779 25

ACCEPTED MANUSCRIPT

696

Salim, S., Ali, A.S., Ali, S.A., 2012. On the role of histamine receptors in regulating pigmentary responses

697

in Oreochromis mossambicus melanophores. J Recept Signal Transduct Res 32, 314–320.

698

doi:10.3109/10799893.2012.729061

701 702

RI PT

700

Salim, S., Ali, S.A., 2011. Vertebrate melanophores as potential model for drug discovery and development: a review. Cell Mol Biol Lett 16, 162–200. doi:10.2478/s11658-010-0044-y Salinas, I., 2015. The Mucosal Immune System of Teleost Fish. Biology (Basel) 4, 525–539. doi:10.3390/biology4030525

SC

699

Salinas, I., Parra, D., 2015. Fish mucosal immunity: intestine. In: Mucosal health in aquaculture, ed. by

704

Beck BH, Peatman E. Ed. Academic Press ISBN: 978-0-12-417186-2, 135-170 pp

705

Schmale, M.C., Vicha, D., Cacal, S.M., 2004. Degranulation of eosinophilic granule cells in

M AN U

703

706

neurofibromas and gastrointestinal tract in the bicolor damselfish. Fish Shellfish Immunol 17,

707

53–63. doi:10.1016/j.fsi.2003.12.002

709 710

Schubert, M.L., 2015. Functional anatomy and physiology of gastric secretion. Curr Opin Gastroenterol 31, 479–485. doi:10.1097/MOG.0000000000000213

TE D

708

Seifert, R., Höer, A., Schwaner, I., Buschauer, A., 1992. Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and

712

induces functional differentiation. Mol Pharmacol 42, 235–241.

714 715 716 717 718 719

Shin, J.S., Abraham, S.N., 2001. Co-option of endocytic functions of cellular caveolae by pathogens. Immunology 102, 2–7.

AC C

713

EP

711

Smolinska, S., Jutel, M., Crameri, R., O’Mahony, L., 2014. Histamine and gut mucosal immune regulation. Allergy 69, 273–281. doi:10.1111/all.12330

St John, A.L., Abraham, S.N., 2013. Innate immunity and its regulation by mast cells. J Immunol 190, 4458–4463. doi:10.4049/jimmunol.1203420 Sundvik, M., Kudo, H., Toivonen, P., Rozov, S., Chen, Y.C., Panula, P., 2011. The histaminergic system

720

regulates wakefulness and orexin/hypocretin neuron development via histamine receptor H1 in

721

zebrafish. FASEB J 25, 4338–4347. doi:10.1096/fj.11-188268 26

ACCEPTED MANUSCRIPT

722

Tacchi, L., Musharrafieh, R., Larragoite, E.T., Crossey, K., Erhardt, E.B., Martin, S.A., LaPatra, S.E.,

723

Salinas, I., 2014. Nasal immunity is an ancient arm of the mucosal immune system of

724

vertebrates. Nat Commun 5, 5205. doi:10.1038/ncomms6205 Vallejo, A.N., Ellis, A.E., 1989. Ultrastructural study of the response of eosinophil granule cells to

RI PT

725 726

Aeromonas salmonicida extracellular products and histamine liberators in rainbow trout

727

Salmo gairdneri Richardson. Dev Comp Immunol 13, 133–148.

728

Vicha, D.L., Schmale, M.C., 1994. Morphology and distribution of eosinophilic granulocytes in

damselfish neurofibromatosis, a model of mast cell distribution in neurofibromatosis type 1.

730

Anticancer Res 14, 947–952.

SC

729

Vukman, K.V., Visnovitz, T., Adams, P.N., Metz, M., Maurer, M., O’Neill, S.M., 2012. Mast cells cultured

732

from IL-3-treated mice show impaired responses to bacterial antigen stimulation. Inflamm Res

733

61, 79–85. doi:10.1007/s00011-011-0394-6

735 736

Werner, K., Neumann, D., Seifert, R., 2014. Analysis of the histamine H2-receptor in human monocytes. Biochem Pharmacol. doi:10.1016/j.bcp.2014.08.028

Winter, S.E., Thiennimitr, P., Winter, M.G., Butler, B.P., Huseby, D.L., Crawford, R.W., Russell, J.M.,

TE D

734

M AN U

731

Bevins, C.L., Adams, L.G., Tsolis, R.M., Roth, J.R., Bäumler, A.J., 2010. Gut inflammation

738

provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429.

739

doi:10.1038/nature09415

741 742

Yamaguchi, T., Tashiro, K., Tanaka, S., Katayama, S., Ishida, W., Fukuda, K., Fukushima, A., Araki, R., Abe, M., Mizuguchi, H., Kawabata, K., 2013. Two-step differentiation of mast cells from

AC C

740

EP

737

induced pluripotent stem cells. Stem Cells Dev 22, 726–734. doi:10.1089/scd.2012.0339

743

Yang, R., Lao, Q.C., Yu, H.P., Zhang, Y., Liu, H.C., Luan, L., Sun, H.M., Li, C.Q., 2015. Tween-80 and

744

impurity induce anaphylactoid reaction in zebrafish. J Appl Toxicol 35, 295–301.

745 746 747

doi:10.1002/jat.3069 Yang, X.D., Ai, W., Asfaha, S., Bhagat, G., Friedman, R.A., Jin, G., Park, H., Shykind, B., Diacovo, T.G., Falus, A., Wang, T.C., 2011. Histamine deficiency promotes inflammation-associated

27

ACCEPTED MANUSCRIPT

748

carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+

749

immature myeloid cells. Nat Med 17, 87–95. doi:10.1038/nm.2278 Zendehdel, M., Baghbanzadeh, A., Aghelkohan, P., Hassanpour, S., 2015. Lipopolysaccharide and

751

histaminergic systems interact to mediate food intake in broilers. Br Poult Sci.

752

doi:10.1080/00071668.2015.1099613

753

RI PT

750

Zhou, Y., Tung, H.Y., Tsai, Y.M., Hsu, S.C., Chang, H.W., Kawasaki, H., Tseng, H.C., Plunkett, B., Gao, P., Hung, C.H., Vonakis, B.M., Huang, S.K., 2013. Aryl hydrocarbon receptor controls murine

755

mast cell homeostasis. Blood 121, 3195–3204. doi:10.1182/blood-2012-08-453597

SC

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Fig. 1

Seconds

Heart

Gut

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Survival for long periods & Proliferate if needed

Weeks

Preformed mediators: Piscidines (I, II, III & IV) Proteases Histamine

Vertebrate Fish Osteichtyes Actinopterygii Perciforms

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Hours Newly synthesized mediators with specific targets (Pathogens): Several cytokines and chemokines

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Mediators without transcription required: Prostaglandins, etc.

SC Replenish granules

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Lamina propia

Epithelium

MCs Activators Mucus hydrogel

Fig. 2

Blood vessel

H2R

Goblet Cell

Mast Cell

Polarization

Acidophilic Granulocyte

Contraction

Lymphocyte T, B or IEL

Activation

Epithelial Cell

H2R

H2R

Innate Lymphoid cell 2

? Antigen

Recruitment

Cytokines Chemokines NADPH

Synthetic Mediators

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IL- 1b Recruitment TNFa

Complement IgM/IgT-antigen complex

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NFkB

MyD88

TLRs

Specific PAMPs

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Macrophage

IL- 5 IL- 9 IL-13

Mucine

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IL-25 IL-33

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Diverse Parasites

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