Link between mast cells and bacteria: Antimicrobial defense, function and regulation by cytokines

Medical Hypotheses 106 (2017) 10–14

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Link between mast cells and bacteria: Antimicrobial defense, function and regulation by cytokines Pio Conti a,⇑, Francesco Carinci b, Alessandro Caraffa c, Gianpaolo Ronconi d, Gianfranco Lessiani e, Theoharis C. Theoharides f a

Immunology Division, Postgraduate Medical School, University of Chieti-Pescara, Chieti, Italy Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy University of Perugia, Perugia, Italy d Clinica dei Pazienti del Territorio, Policlinico Gemelli, Roma, Italy e Internal Medicine, Villa Serena Hospital, Città Sant’Angelo, Italy f Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative, Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA b c

a r t i c l e

i n f o

Article history: Received 10 February 2017 Accepted 25 June 2017

Keywords: Mast cells Cytokines Chemokines Pathogens Bacteria

a b s t r a c t Bacteria and their products, such as LPS, act on mast cells (MCs) to induce the secretion of multiple cytokines, including IL-1, TNF, IL-18 and IL-33, which can be dosed in the site of infected tissues. Antigen-binding IgE cross-links FceRI on mast cells involves the generation and activation of PKCd, ERK, tyrosine kinases (Syk and Lyn) and mitogen-activated protein kinases (MAPKs), inducing the release of chemical mediators which provoke inflammation and hypersensitive reaction. Other stimuli, including, cytokines, neuropeptides, chemical and physical activators, can also act on MCs to release a plethora of inflammatory compounds. Activated MCs produce a broad spectrum of inflammatory cytokines, chemokines, lipid compounds and vasoactive amines, all involved in immune response. By producing TNF, MCs have an antibacterial defense and a protective function; while pathogenic bacteria and their products, such as LPS, have an inflammatory response through MC activation. LPS binding TLR4 produce MC generation IL-1 family members, and chemokines, which may recruit inflammatory cells at the infection site; whereas in KitW/W-v mice, where MCs are genetically absent, the inflammatory effect is not present. We report for the first time a link between MCs and bacteria emphasizing the mediation of inflammatory cytokines/chemokines. We can conclude that mast cells fight bacteria, and their immune response is perfectly integrated in the immune network. We hope that the understanding of microbial and mast cell interaction leads to more efficient therapeutic development in relation to microbial resistance. Ó 2017 Elsevier Ltd. All rights reserved.

Introduction According to the recently published international consensus, study on the involvement of mast cells (MCs) in human biology and human diseases is increasing and involves more and more researchers. The body of a healthy human possesses microorganisms ten times higher than the number of human somatic cells. There are about three hundred trillion bacteria in the intestine and one hundred trillion on our skin [1].

⇑ Corresponding author at: Postgraduate Medical School, University of Chieti, Viale Unità d’Italia 73, Chieti 66013, Italy. E-mail address: [email protected] (P. Conti). http://dx.doi.org/10.1016/j.mehy.2017.06.018 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.

Some bacteria are beneficial to humans and some can provoke disease, whereas others are opportunistic guests that wait for the immune system to decrease before becoming pathogenic [2]. In this paper we report for the first time a link between MCs and bacteria, including some of their products. The response to infection is crucial for the survival of an organism. Bacteria can cause disease by invasiveness, attacking and damaging the host cells, or by generating toxic compounds that poison the host cells. Certainly, many host defenses, including cellular immunity provided by macrophages, neutrophils, lymphocytes, eosinophils and MCs, are involved in fighting bacteria, a complex cascade of immunological events [3,4]. However, professional phagocytes, such as polymorphonuclear granulocytes and mononuclear phagocytes, are the major effectors of anti-bacterial defense.

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Some bacteria may release compounds, such as kinases, hyaluronidase, hemolysins, coagulases, which are not considered bacterial toxins but exert important effects and affect the host [5]. Endotoxins and exotoxins are bacteria toxins, generated by certain Gram-negative and Gram-positive bacteria, which are considered very potent poisons. Endotoxins are found in Gram-negative bacteria and are lipopolysaccharides (LPS) present in the cell envelope with less specific actions compared with exotoxins. LPS is released by the bacterial cell wall and is of great significance, not only for immunological reaction but also for therapeutic intervention [6]. When antigen-presenting cells (APC) encounter microbial products such as LPS they respond by expressing high levels of B7-1 and B7-2 which stimulate the response of T lymphocytes [7]. The binding of LPS to antigen-presenting cells and MCs produces cytokines and chemokines which promote the growth and differentiation of T cells [8]. MCs respond to many bacteria, including intracellular microorganisms and bacterial products (i.e. LPS), by generating inflammatory mediators [9,10]. Bacteria, and LPS, as well as other microbial compounds and signals, also activate macrophages which release IL-1-cytokine family members, including IL-1, IL-18 and IL-33, which trigger innate immunity [11]. LPS directly stimulates and activates MCs which release a plethora of inflammatory compounds including cytokines, which participate in innate immunity [12]. These cytokines exert an acute inflammatory action involving endothelial cells and leukocytes [13]. Inhibition of MCs producing cytokines reduces the pathologic complications of sepsis and diminishes the mortality associated with septic shock [14]. In addition, infections involve macrophages and T cells to produce IFNs which function to inhibit viral replication, and also exert important effects on MCs [15]. Microbial stimulus, including LPS in activating the innate immune reactions, provokes the release of IL-12 and IFN-c generated by NK cells and T lymphocytes [16]. LPS binding to TLR4 activates MCs to induce and release mRNA expression of IL-4, IL-5 and IL-13, which in turn can provoke specific chemokine generation that causes the recruitment of inflammatory cells by increasing inflammation [17]. Presentation and testing of the hypothesis IL-1 cytokine family members, such as IL-1, IL-18, IL-33, and IL-36, play a fundamental role in the initiation and amplification of immune responses. However, at the present time we do not know how many new IL-1 family members exist, and how differently they act on mast cells. The hypothesis is that there are many IL-1 inflammatory cytokines that act in different ways. During bacterial infection, IL-1 released by macrophages and MCs increases (Fig. 1), leading to resistance of infections, and treatment with anti-IL-1 receptor antibody exacerbates the infection;

Fig. 1. Mast cell generation from hematopoietic stem cell.

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while infected mice treated with recombinant IL-4 have reduced bacterial growth and inflammation. IL-8, a CXC chemokine, which is important for mast cell functions and has the capacity to attract neutrophils to the site of inflammation, is generated by macrophages and is activated in the infected human body. TLRs are proteins that enhance certain cytokine gene expressions in response to various pathogenic ligands and are involved in innate and adaptive immune responses [18,19]. TLR4 is a receptor for LPS which plays an important role in inflammation and is a risk factor for asthma mediated by MCs [20,21]. Activation of TLR4 by LPS on MCs leads to Th2 cytokine generation which enhances allergic inflammation, an effect also mediated by chemokines [22]. In fact, CD4+ T cells, which are in a consistently elevated number in allergic tissue, are the primary orchestrators of the specific immune response implicated in the pathogenesis of allergic disorders [23]. T-cell activation increases the expression of IL-2 receptor (IL-2R), class II histocompatibility antigen (HLA-DR) and very late activation antigen (VLA 1–6) in allergic tissues, effects that can be inhibited by IL-35 [24]. It is believed that these effects are due to the presence of MCs, since LPS-mediated enhancement inflammation is not observed in genetically W/Wv mice, where MCs are absent [25]. Therefore, MCs control allergic inflammation through the activation of TLR4 that mediates the induction of GATA1 proteins, resulting in increased Th2 cytokine generation [12]. GATA1 was identified in nuclear protein from MCs as GATA motif-binding protein which controls human ST2 gene transcription, a receptor for IL-33 which modulates the Th2 response [26]. Mast cells were first described in the frog mesentery in the middle of the 19th century. They are multifunctional immune cells ubiquitous in the body, located preferentially around blood vessels, in connective tissue and in intraepithelial locations, and are the first line of defense [27,28]. Data and discussion MCs are activated through cross-linking of their surface high affinity receptors for IgE (FceRI), leading in seconds to degranulate and release stored mediators such as histamine, heparin, tryptase, chymase, kinogenases, carboxypeptidase A3 and TNF, and/or de novo later synthesized inflammatory compounds, such as growth factors, leukotrienes, prostaglandins, NO, and cytokines/chemokines [29]. Activated MCs release vasoactive mediators as well as chemotactic factors that promote leukocyte infiltration and exacerbate the inflammatory response [30]. A number of stimuli, especially engagement of receptors for the Fc portion of Ig (FcR), can activate MCs, and cross-linking of the FceRI on its surface induces the release of biologically active preformed mediators [31,32]. MCs are mostly implicated in the pathogenesis of allergic diseases but they also perform important beneficial roles in host defense and in natural immunity to bacterial infection [33]. In addition, they participate in acquired immunity, inflammation, autoimmunity, metabolic disorders and infectious diseases [34]. In recent years, MCs have been seen to participate in pathological processes associated with classical inflammation without degranulation [35]. MCs FceRI high affinity receptor for immunoglobulin E [(IgE) (Kd = 10 10 M)] activation leads to the involvement of several cytoplasmic protein tyrosine kinases such as Syk and Lyn, and recruitment of adaptor molecules including PI3K/Akt, PLCgamma/Ca2+/PKC and Grb2/SOS/Raf-1/mitogen-acti vated protein kinase (MAPK) pathways [36]. Secretory molecules of the bacterial secretion system amplify the TLR signaling response by activating NFrB and/or MAPKs [37]. MAPKs, in turn, result in the induction of transcription factors AP-1 and c-fos and activate cytokine gene expression with the production of mRNA

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cytokine which leads to the generation of inflammatory cytokines [38]. The transcription factors are very important and powerful, as they control the reprogram of differentiated cells from one cell type to become another cell, generating a new type of cells [39]. However, since KitW/W-v mice, where MCs are genetically absent, are more vulnerable to bacterial infection, it is likely that the presence of mast cells in the body is important against infections, and for the clearance of bacterial pathogens [25]. Therefore, antigens, or neuropeptides stimulate MCs which leads to the activation and generation of tyrosine kinases, PI3K, ERK, JNK, MAPK, NF-jB and PKCd [40]. MCs synthesize and secrete over 50 biological compounds including chemical mediators and cytokines/chemokines. TNF, which is released by MCs and other immune cells, is the principal mediator of septic shock. IL-1, IL-2 and IFN-c synergize with LPS Gram-negative bacteria to activate macrophages in generating TNF [41] Moreover, the cytokine IL-9 and SCF interact with MCs through their tyrosine kinase receptor c-Kit, and several c-Kit inhibitors to maintain the production and survival of MCs [42]. MCs may also produce anti-inflammatory cytokines, including interleukin IL-4, IL-10 and IL-13 [43]. These cytokines play an important role in the pathogenesis of allergy, inflammation and infectious diseases. Therefore, through multiple mechanisms, MCs have an antibacterial defense and a protective function. In fact, they generate TNF and protease which directly kill bacteria and degrade pathogenic toxins [44,45]. Furthermore, with their production of chemokines CCL2 and CXCL1, and leukotrienes LTC4, MCs attract neutrophils to the site of the bacterial infection, generating inflammation [46]. MCs release anti-bacterial TNF, and other cytokines/chemokines, which lead to the stimulation and promotion of the migration of APC, activated by pathogenic bacteria, with the consequent release of inflammatory cytokines which are also involved in the stimulation of the cellular immune system including T and B lymphocytes [47]. Endogenous TNF superfamily ligands can be active as membrane-form, such as CD40L, FasL, OX40L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or are generated and active through oligomerization by the binding of proteoglycans at the cell membrane, such as a proliferation inducing ligand (APRIL), a member of the TNF ligand superfamily [48]. Therefore, receptors and ligands of the TNF superfamily are therapeutically important targets in a human diseases, including autoimmunity and inflammation [48]. MCs cross-talk with stimulated B cells to generate immune molecules such as IL-4, IL-13, and CD40L which are implicated in the synthesis of IgE [49,50]. This production can be completely inhibited by anti-IL-4 or anti-IL-13 or with soluble CD40. Upon stimulation, MCs release considerable amounts of cytokines/ chemokines, including IL-4, which participate in the induction of T-cell differentiation such as Th2 cells, NK1.1+ cells and cd+T cells, which also generate IL-4 [51,52]. MCs are involved in the ingesting and killing of adherent bacteria in a manner not unlike that of traditional phagocytic cells such as macrophages or neutrophils. The classic immunological functions of MCs are currently considered to be the main cells of the allergic reaction, but they are also involved in innate and adaptive immunity and inflammation. There is considerable evidence suggesting that MCs play a crucial role in bacterial inflammatory diseases. Activation of T cells, macrophages, and MCs generate and release a sequential cascade of inflammatory products, such as inflammatory IL-1, TNF, IL-18, IL-32 and IL-33, reactive oxygen intermediates and platelet activating factor (PAF) [43]. However, bone marrow murine mast cells are stimulated by IL-15, whereas they do not respond to IL-2, which shares the IL-2Rb and IL-2Rc but not IL-2Ra [53].

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, proinflammatory and proliferative endothelial cell-derived peptide, important for the regulation of vascular function, secreted by endothelial cells [54]. It acts through two types of receptors, ETA and ETB, causing fibrosis of the vascular cells, increasing superoxide anion production, activation of transcription factor NF-jB, and expression of pro-inflammatory Th1 cytokines, including TNF and IL-1 family members, an effect that can be inhibited by treatment with IL-10 [55,56]. ET-1 is also involved in endotoxaemia associated with morbidity and mortality due to septic infections [57]. MCs can be activated by several factors, including ET-1, which binds its ET(A) receptor [58]. This effect may cause the degranulation of MCs that pours on the tissues many inflammatory substances, including MC-associated chemical mediators, cytokines/chemokines and arachidonic acid products [52]. MCs are implicated in natural immunity against pathogens including bacteria which can activate them to release chemokines such as ‘regulated on activation normal T-cell expressed and presumably secreted’ [RANTES (CCL5)] and MCP-1(CCL2) [59]. Several chemokines are involved in the recruitment of inflammatory cells in inflammatory disorders and work through G-protein coupled receptors. We previously showed for the first time, in an experimental animal model, that RANTES and/or MCP-1, two inflammatory chemokine mediators, injected intramuscularly or intradermally in normal rats strongly provoke an inflammatory response; while injected into genetically mast cell-deficient W/ Wv rats do not induce any inflammatory reaction (41]. This suggests the importance of these two chemokines in attracting MCs to the inflammatory site. In addition, vitamin 1,25-(OH)2D3 is known to have an immunoregulatory role mediated through binding to the vitamin D receptor in immune cells, including MCs [60]. It has been reported that 1,25-(OH)2D3 induces the expression of NOS2, an observation that identifies NO as the putative anti-bacterialeffector produced by MCs [61]. The intestinal immune system is associated with gut microbiota for maintaining the physiological function of the intestine. The lack of balance between the immune system of the intestinal bacteria leads to inflammatory diseases. However, the mechanisms by which the immune system maintains this critical balance is still unclear. For instance, it has been recently reported, that there are some products, such as short-chain fatty acid n-butyrate secreted in high amounts by commensal bacteria, which can modulate the function of gut immunity. This compound may inhibit TNF, IL-6 and certain chemokine generation by FceRI activated murine mast cells [62]. Galactin-9, a microbial carbohydrate product, is a member of galactin family, widely distributed in several cell types with a wide spectrum of biological functions such as modulation of cell differentiation, adhesion, aggregation and cell death. Galectin-9 regulates multiple physiological and pathological functions including allergy. MCs augment the expression of galectin-9 in intestinal epithelial cells. Blocking the ligand TIM-3 of galactin-9 results in amelioration of allergy including asthma [63]. MCs also participate in the immune response to Mycoplasma pneumoniae, a bacteria that lacks a classical bacterial cell wall. In fact, MCs protect from pneumonia and from the augmentation of bacteria in the lungs, demonstrating that they play an important function in innate immune response [64,65] against harmful bacteria to the lungs [66,67]. Some broad-spectrum antibacterial agents, which have previously been shown to alleviate allergy and inflammation, may inhibit mast cell function and degranulation, but the mechanism of action is still unknown. Forsythe P. et al. reported in an interesting article that certain strains lactobacillus can have systemic immune functions that

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Fig. 2. Mast cell activation cascade through TLR leads to early degranulation and causes inflammation. Late release of cytokines and arachidonic acid compounds also provoke inflammatory states.

include the attenuation of allergic responses, an effect probably due to MC stabilization [68]. All studies reported here (Fig. 2) are interesting and help to better clarify the role of MCs in bacterial infections; however, the biological role of MCs and their mediators, including cytokines and chemokines, in response to pathogenic microorganisms is still largely unknown. Furthermore, in future studies, we hope to improve the specific inflammatory response provoked by pathogenic bacteria and/or their products, through the manipulation of MCs or microbes and specific inflammatory cytokine blockage. Further ideas for testing In the future, there are many ideas to test, one for example is to see how many cytokines and chemokines are produced by microbe stimulated MCs. Again, it would be interesting to study the specificity of microbes on the activation of MCs. Financial disclosure The authors have no funding to disclose. Conflict of interest All the authors report no conflicts of interest relevant to this article. References [1] Theoharides TC. On the gut microbiome-brain axis and altruism. Clin Therapeutics 2015;37(5):937940.

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