Emerging roles of basophils in allergic inflammation

Allergology International xxx (2017) 1e10

Contents lists available at ScienceDirect

Allergology International journal homepage: http://www.elsevier.com/locate/alit

Invited review article

Emerging roles of basophils in allergic inflammation Kensuke Miyake*, Hajime Karasuyama Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 April 2017 Received in revised form 12 April 2017 Accepted 13 April 2017 Available online xxx

Basophils have long been neglected in immunological studies because they were regarded as only minor relatives of mast cells. However, recent advances in analytical tools for basophils have clarified the nonredundant roles of basophils in allergic inflammation. Basophils play crucial roles in both IgE-dependent and -independent allergic inflammation, through their migration to the site of inflammation and secretion of various mediators, including cytokines, chemokines, and proteases. Basophils are known to produce large amounts of IL-4 in response to various stimuli. Basophil-derived IL-4 has recently been shown to play versatile roles in allergic inflammation by acting on various cell types, including macrophages, innate lymphoid cells, fibroblasts, and endothelial cells. Basophil-derived serine proteases are also crucial for the aggravation of allergic inflammation. Moreover, recent reports suggest the roles of basophils in modulating adaptive immune responses, particularly in the induction of Th2 differentiation and enhancement of humoral memory responses. In this review, we will discuss recent advances in understanding the roles of basophils in allergic inflammation. Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access

Keywords: Basophil IgE-mediated chronic allergic inflammation IL-4 Protease Th2 differentiation Abbreviations: 5-LOX, 5-lipoxygenase; AD, atopic dermatitis; APC, antigen-presenting cell; APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor; CIU, chronic idiopathic urticaria; COX, cyclooxygenase; DC, dendritic cell; DT, diphtheria toxin; EGF, epidermal growth factor; EoE, eosinophilic esophagitis; EMA, European Medicines Agency; FcRg, Fc receptor common g-chain; FDA, Food and Drug Administration; GFP, green fluorescence protein; GPCR, G proteincoupled receptor; IgE-CAI, IgE-mediated chronic allergic inflammation; ILC2, group 2 innate lymphoid cell; Lm, Listeria monocytogenes; LPS, lipopolysaccharide; MHC-II, major histocompatibility complex class II; mMCP-11, mouse mast cell protease 11; Nb, Nippostrongylus brasiliensis; OVA, ovalbumin; PAF, platelet-activating factor; PGN, peptidoglycan; PspA, pneumococcal surface protein A; SLE, systemic lupus erythematosus; TLR, Toll-like receptor; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin; VCAM-1, vascular cell adhesion molecule-1; WT, wild-type

article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction * Corresponding author. Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. E-mail address: [email protected] (K. Miyake). Peer review under responsibility of Japanese Society of Allergology.

Basophils are the least common granulocytes, representing less than 1% of peripheral blood leukocytes in both mice and humans. Basophils share some features with tissue-resident mast cells,

http://dx.doi.org/10.1016/j.alit.2017.04.007 1323-8930/Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

2

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

including basophilic granules in their cytoplasms and expression of the high-affinity IgE receptor FcεRI on their cell surfaces.1 Therefore, basophils have long and erroneously been considered to serve redundant roles with mast cells. Nevertheless, basophils and mast cells differ in several aspects, including their localization and life span.1,2 Basophils circulate in the peripheral blood and migrate to sites of inflammation, whereas mast cells reside in the peripheral tissues and are rarely detected in blood. Moreover, the life span of basophils (~60 h) is much shorter than that of mast cells (2e3 weeks). Despite these differences that suggest functional differences between basophils and mast cells, the non-redundant roles of basophils have not been identified until recently, partly because of the rarity of basophils and lack of tools for basophil research. The recent development of novel analytical tools, including basophildepleting antibodies and genetically-engineered mice deficient for basophils, have revealed non-redundant functions of basophils in various immune responses such as chronic allergic inflammation and protective immunity against parasites.3e5 Moreover, a recent report showed that expression profiles of basophils are much different from those of mast cells,6 indicating their distinct roles in immune responses. In this review, we focus on recent advances in our understanding of basophils in allergic inflammation. Roles of basophils in allergic inflammation IgE-dependent allergic inflammation IgE-mediated chronic allergic inflammation(IgE-CAI) in the skin Infiltration of basophils into inflammatory sites has been reported in various types of allergic inflammation, including atopic dermatitis, allergic rhinitis, and asthma.7e9 However, until recently, the contribution of basophils in allergic reactions has remained

obscure. Our group has identified non-redundant roles of basophils in a mouse model of IgE-CAI.10e12 In this model, mice were passively sensitized with antigenspecific IgE and then their ears were subcutaneously injected with antigens. Consequently, mice exhibited mast cell-dependent biphasic ear swelling (comprising immediate-phase and latephase ear swelling), followed by severe ear swelling that peaked on days 3e4 after challenge. This delayed-onset ear swelling accompanied massive infiltration of inflammatory cells, including eosinophils, neutrophils, and macrophages, and hyperplastic epidermis with hyperkeratosis. We designated this delayed-onset response IgE-CAI. IgE-CAI can be elicited even in the absence of mast cells or T cells, suggesting that neither mast cells nor T cells are essential for the development of IgE-CAI. Importantly, adoptive transfer of basophils into FcεRI-deficient mice can reconstitute IgECAI, even though basophils account for only ~2% of skin-infiltrating cells, demonstrating the pivotal role of basophils in this reaction. Later studies further confirmed the indispensable role of basophils in IgE-CAI by using basophil-specific depletion antibody (antiCD200R3 antibody (Ba103)) or genetically engineered-mice that specifically lack basophils (Mcpt8Cre mice, diphtheria toxin (DT)treated Mcpt8DTR mice, and DT-treated Bas-TRECK mice).11e14 Notably, depletion of basophils even during the progress of inflammation resulted in the suppression of ear swelling and a drastic reduction in inflammatory cell infiltration, suggesting the effectiveness of basophil-targeted therapy.11 Therefore, basophils appear to act as initiators of inflammation, recruiting other inflammatory cells such as eosinophils and neutrophils. We postulate the following scenario in IgE-CAI pathogenesis (Fig. 1); First, a small number of basophils are recruited to skin lesions by unknown mechanisms. IgE-bound basophils are activated by antigens, causing the release of various inflammatory mediators, including

Fig. 1. Roles of basophils as initiator of chronic allergic inflammation. In antigen-sensitized mice, circulating basophils are armed with antigen-specific IgE. After administration of antigens into ear skin, a small number of basophils infiltrate into skin lesions and activated by antigens, leading to the release of a variety of mediators. Cytokines and other mediators produced by activated basophils acts on skin-resident cells, including fibroblasts, endothelial cells, and ILCs. Stimulated skin-resident cells secrete substantial amount of chemokines, promoting the migration of inflammatory cells, including neutrophils, eosinophils, monocytes and basophils. On the other hand, basophil-derived serine proteases such as mMCP-11 act on serum proteins to generate chemotactic factors, leading to the recruitment of inflammatory cells. Thus basophil-derived inflammatory mediators induce further recruitment of inflammatory cells, leading to chronic allergic inflammation.

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

cytokines, chemokines, and proteases. Basophil-derived mediators may act on skin-resident cells (fibroblasts, endothelial cells, and others), leading to the recruitment of large number of inflammatory cells. Basophil-derived proteases generate chemotactic factors by acting on serum proteins, which can induce further basophil infiltration, as described in a later section. Thus, the infiltration of small numbers of basophils leads to the aggravation of inflammation. Basophils are required to migrate from blood to tissue, and therefore basophil-dependent inflammation may show a delayed onset, in contrast to acute-onset mast cell-dependent inflammation. Basophils have been shown to play essential roles in IgEdependent skin allergy models other than IgE-CAI.15,16 Likewise, in the course of repeated parasitic infections, IgE-armed basophils infiltrate into sites of infection and play key roles in generating protective immunity against parasites in an IgE-dependent manner.17,18 IgE-dependent airway inflammation e rhinitis and asthma In addition to skin inflammation, basophils contribute to several models of IgE-dependent airway inflammation. Recent reports have shown that depletion of basophils improves rhinitis symptoms in models of allergic rhinitis.19,20 In one model, mast cells are also crucial for the development of allergic rhinitis,21,22 and it is assumed that sequential engagement of mast cells and basophils is important to elicit nasal immune responses.20 Allergen exposure stimulates mast cells in nasal mucosa to release histamine, which acts on the histamine H4 receptor on basophils, leading to migration of basophils into nasal tissues. Activated basophils in nasal tissues release various mediators to induce both early- and latephase nasal reactions. In contrast to the allergic rhinitis model, the role of basophils remains ill-defined in the IgE-dependent allergic asthma model. One report indicated that mast cells, but not basophils, are essential for the development of airway inflammation in allergic asthma,13 whereas other reports have shown the importance of basophils in airway inflammation and Th2 responses.23,24 These reports suggest that the relative importance of basophils and mast cells in allergic asthma differs depending on experimental conditions. Because basophils play crucial roles in delayed-onset responses in IgE-CAI, it can be postulated that basophils may also play important roles in asthma models using chronic allergen challenge. Human allergic disorders Whether basophils play crucial roles in human allergic disorders remains unclear. However, recent clinical experiences with anti-IgE antibody therapies (e.g., Omalizumab) provide some evidence of their role in human diseases. Omalizumab binds to the FcεRIbinding region of IgE, thus preventing interactions between soluble IgE and FcεRI on basophils and mast cells. Downregulation of FcεRI expression on basophils occurs within 2 weeks, whereas that on mast cells typically occurs after 8 weeks.25,26 Therefore, it is expected that the therapeutic effects of omalizumab in basophilmediated allergic reactions can be observed as early as 1e2 weeks. Chronic idiopathic urticaria (CIU) is defined as itchy hives that last for at least 6 weeks and that have no apparent external trigger. Although H1-antihistamines are widely prescribed for the initial treatment of patients with CIU, the majority of patients do not respond to these drugs, even at the maximum licensed dose.27 Recently, the administration of omalizumab has been shown to diminish the clinical symptoms of CIU in phase 3 clinical trials, and omalizumab is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a novel drug for patients with CIU.28,29 Of note, the therapeutic effects of omalizumab on patients with CIU can be observed within 1 week, suggesting the involvement of basophils in the pathogenesis of CIU.28 Several observations support the role of basophils in CIU.30

3

Patients with CIU present blood basopenia, which is believed to be the result of basophil migration into skin lesions. Consistent with this, a recent report has shown that basopenia is significantly ameliorated with omalizumab treatment.31 Furthermore, basophils in patients with CIU show paradoxical suppression of FcεRI-mediated histamine release, which reverses with disease remission.32 A recent report showed that sera from patients with CIU suppressed the activation of basophils from healthy donors, suggesting that unknown suppressive factors are present in the sera of patients with CIU.33 Taken together, results of these studies suggest that IgE and basophils play essential roles in the pathogenesis of chronic urticaria. In contrast to CIU, contribution of basophils in other IgEmediated human allergic disorders including allergic rhinitis and asthma remain poorly understood, although some evidences suggest the role of basophils in these diseases.7,34,35 IgE-independent allergic inflammation Basophils are also crucial in IgE-independent allergic inflammation in mouse models, including asthma induced by allergenic proteases,36,37 irritant contact dermatitis,38 atopic dermatitis (AD)like skin inflammation,39e41 and eosinophilic esophagitis (EoE)42,43 (Fig. 2). Basophils respond to a variety of innate immune-related stimuli other than IgE with antigen stimulation.44 IL-3, a key cytokine for basophil survival, induces IL-4 production in basophils through interaction with the Fc receptor common g-chain (FcRg) which is constitutively associated with the IL-3 receptor.45 IL-18 and IL-33, members of the IL-1 family of cytokines, also induce IL-4 production in basophils.46 Toll-like receptor (TLR) ligands, including lipopolysaccharide (LPS) and peptidoglycans (PGNs), induce IL-4 production by basophils in the presence of IL-3.47,48 Several allergenic proteases such as papain and house dust mitederived proteases induce activation of basophils.49,50 A recent report showed that extracellular ATP can also modulate basophil activation.51 Recent findings indicate that basophils have two distinct subpopulations depending on cytokine milieu, namely thymic stromal lymphopoietin (TSLP)-elicited basophils and IL-3-elicited basophils.52 TSLP-elicited basophils show higher expression of receptors for IL-3, IL-18, and IL-33, leading to their greater capacity to release IL-4 in response to these cytokines, compared to IL-3elicited basophils. In contrast, TSLP-elicited basophils exhibit less capacity to degranulate upon antigen and IgE stimulation. These results suggest that TSLP-elicited basophils may play roles in IgEindependent basophil activation. Indeed, TSLP plays key roles in most of the IgE-independent allergic reactions mediated by basophils.39e43 TSLP is reported to be highly expressed in keratinocytes from patients with AD, and polymorphisms in TSLP are directly associated with AD.53,54 TSLP upregulation induced by a transgene specifically expressed in skin or repeated application of a chemical can trigger AD-like skin inflammation in mice.55e57 In some TSLPdependent AD models, depletion of basophils results in the amelioration of skin inflammation, suggesting the contribution of TSLP-elicited basophils in these models.39e41 Gain-of-function polymorphisms in TSLP are also associated with EoE, a food allergy-associated inflammatory disease strongly associated with AD.58,59 Mouse models of EoE are established by sensitization with food allergens in barrier-disrupted skin lesions, followed by oral allergen challenge.42,43 Development of EoE in these models is dependent on basophils and TSLP, and basophil infiltrate is detected in esophageal lesions of mice and humans.42,43 Recent study demonstrated the significance of the IL-33-basophil axis in this model.43 Depletion of basophils abolished the

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

4

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

Fig. 2. Involvement of basophils in IgE-dependent and IgE-independent allergic inflammation. Basophils are involved in both IgE-dependent and -independent allergic inflammation. In IgE-dependent allergic inflammation, basophils are activated by antigen and IgE stimulation, causing degranulation and secretion of cytokines. Basophil-derived mediators induce the recruitment of other inflammatory cells, leading to the chronic allergic inflammation in antigen-challenged sites. IgE-independent allergic inflammation mediated by basophils is mostly associated with TSLP. TSLP-elicited basophils are activated by cytokine stimulation, such as IL-3, IL18, and IL-33, leading to the secretion of IL-4. Basophil-derived IL-4 induces the recruitment of inflammatory cells including eosinophils to the site of inflammation.

development of EoE, and EoE was recovered by adoptive transfer of basophils from WT but not IL-33 receptor-deficient mice. Moreover, IL-33 receptor expression is increased in esophagi of patients with EoE.43 Based on these results, it can be postulated that TSLP-elicited basophils infiltrate the esophagus and that basophils activated by IL-33 and other stimuli initiate esophageal inflammation. The significance of basophils and TSLP was also demonstrated in food allergy models induced by epicutaneous sensitization with allergens.40,60,61 TSLP and basophils play key roles in allergenspecific IgE production during the sensitization phase, while mast cells are important for the development of food allergy after challenge. Of note, the significance of TSLP receptors on dendritic cells (DCs) has been demonstrated in one model, which suggests that basophils and DCs work together to induce Th2 cells and IgE production,61 as further discussed in later sections.

induces the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, which facilitates transmigration of eosinophils into inflammatory sites.16 Indeed, basophil-specific IL-4-deficient mice showed impaired induction of VCAM-1 expression on endothelial cells and reduced infiltration of eosinophils in skin lesion. In a papain-induced airway inflammation model, basophil-derived IL-4 stimulates lungresident group 2 innate lymphoid cells (ILC2s), leading to the secretion of larger amounts of IL-5, IL-13, and CCL11, thus inducing the migration of eosinophils.36 Mice that specifically lack basophilderived IL-4 showed reduced secretion of cytokines in ILC2s and impaired recruitment of eosinophils in lungs. Another group has reported similar findings in an allergic skin inflammation model, in which basophil-derived IL-4 induces the activation of skin-resident ILC2s, thus promoting eosinophil migration into skin lesions.41

Basophil-derived effector molecules inducing allergic inflammation

Role of other cytokines/chemokines derived from basophils Besides IL-4, basophils from mice and humans produce various cytokines and chemokines such as IL-6, IL-13, TNF-a, MIP-1a (CCL3), and MIP-1b (CCL4).64 Basophil-derived IL-6 was recently reported to be important for Th17 cell differentiation and humoral memory responses,65,66 but further investigation is required to define the significance of basophil-derived IL-6 in these responses. Roles of other cytokines/chemokines in allergic reactions remain largely unclear. A recent report suggested the contribution of basophil-derived chemokines to tumor rejection.67 During the rejection of melanoma tumors, depletion of regulatory T cells (Treg) induces infiltration of basophils into tumors, which promotes CD8þ T cell recruitment by basophil-derived CCL3 and CCL4, resulting in efficient rejection of tumors. In addition to the cytokines mentioned above, basophils can also produce amphiregulin, an epidermal growth factor (EGF)-like cytokine, upon stimulation with IL-3 produced by T cells.68 Basophil-derived amphiregulin is a key participant in UVB irradiation-induced immune suppression by enhancing the suppressive function of Treg cells.69

Although it is now widely appreciated that basophils contribute to several mouse allergy models62,63 as described above, it has remained unclear how basophils induce inflammation after activation. Recently, several studies shed some light on this issue. In this section, we will focus on the effects of basophil-derived cytokines, proteases, and other mediators on allergic inflammation. Cytokines and chemokines Role of basophil-derived IL-4 in allergic inflammation Both mouse and human basophils are known to produce large quantities of IL-4 in response to various stimuli. Roles of basophilderived IL-4 in allergic inflammation have been extensively studied in recent years. Several lines of evidence indicate that basophilderived IL-4 acts on a variety of cell types to induce eosinophil infiltration (Fig. 3). Indeed, basophil depletion leads to reduced eosinophil recruitment to the site of inflammation in several allergy models.16,36,38 In a co-culture system, basophil-derived IL-4 and TNF-a stimulate fibroblasts to secrete eotaxin-1 (CCL11) and RANTES (CCL5), causing the migration of eosinophils.38 In an IgEdependent skin inflammation model, basophil-derived IL-4

Effects of basophil-derived proteases on allergic inflammation Both basophils and mast cells store serine proteases in their granules and release them in response to various stimuli.

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

5

Fig. 3. Versatile roles of basophil-derived IL-4 in allergic inflammation. Basophils can produce large amount of IL-4 in response to a variety of stimuli. In the early phase of inflammation, basophil-derived IL-4 acts on skin-resident cells, including fibroblasts, endothelial cells, and ILCs, leading to the accumulation of eosinophils to the site of inflammation. In the later phase of inflammation, basophil-derived IL-4 acts on inflammatory monocytes, leading to the differentiation into M2 macrophages. M2 macrophages promote either resolution of allergic inflammation or protective immunity against helminthic parasites.

Importantly, recent studies have revealed that basophils and mast cells in mice possess different serine proteases. We and other groups have found that basophils rather than mast cells preferentially express mouse mast cell protease 11 (mMCP-11) and mMCP-8, while mMCP-6 and mMCP-7 are selectively expressed by mast cells.70,71 The roles of mast cell-selective mMCP-6 and mMCP-7 have been extensively studied, and these proteases play significant roles in protection against bacterial infections and the development of inflammatory diseases. In contrast, the physiological significance of basophil-selective mMCP-8 and mMCP-11 has remained elusive until recently. We found basophil-derived tryptase mMCP-11 plays crucial roles in IgE-CAI responses72 (Fig. 4). mMCP-11-deficient mice showed an ameliorated IgE-CAI response, with reduction in ear swelling, microvascular permeability, and infiltration of leukocytes, including eosinophils, neutrophils, and macrophages. In addition, injection of recombinant mMCP-11 protein into mouse ears induced cutaneous ear swelling with increased microvascular permeability, and three consecutive injections of recombinant protein induced cellular infiltration.72,73 Of note, mMCP-11 also induces leukocyte recruitment in a transwell migration assay in vitro. Based on observations that this leukocyte migration requires serum in culture media and that this migration activity in response to mMCP-11 is dependent on protease activity, mMCP-11 appears to cleave serum proteins, and proteolytic products induce the migration of leukocytes, including basophils. Inhibitor experiment further revealed that mMCP-11-elicited leukocyte migration is dependent on G protein-coupled receptors (GPCRs). These findings indicate that mMCP-11, which is released from basophils upon degranulation, promotes further migration of basophils, leading to further release of mMCP-11 in affected tissues.

Our recent report determined the function of mMCP-8 using recombinant proteins74 (Fig. 4). Similar to mMCP-11, administration of mMCP-8 into mouse ears induced ear swelling with increased microvascular permeability and leukocyte infiltration in a protease activity-dependent manner. However, unlike mMCP-11, mMCP-8 did not possess chemotactic activity in vitro, but rather induced chemokine expression in skin-resident cells to induce leukocyte infiltration. Thus, basophil-derived serine protease mMCP-8 and mMCP-11 cooperatively induce allergic inflammation by promoting increased microvascular permeability and leukocyte infiltration through different mechanisms. Effects of other mediators e histamine, PAF and lipid mediators Histamine is the major chemical mediator stored in granules of basophils. Histamine release from basophils is widely measured in clinical tests for food allergies.75 However, the significance of histamine released from basophils remains ill defined. Indeed, mast cells and histamines play crucial roles in IgE-induced systemic anaphylaxis, whereas basophils are dispensable for this reaction.76 In contrast, basophils play crucial roles in IgG-induced anaphylaxis by releasing platelet-activating factor (PAF). However, following studies also demonstrated the significance of neutrophils and macrophages in IgG-induced anaphylaxis under different experimental conditions,77,78 indicating that the relative contribution of basophils, neutrophils, and macrophages in IgG-dependent anaphylaxis can differ depending on experimental conditions. A recent study indicates that the IgG subclass and its binding capacity to Fcg receptors determine the contribution of basophils, neutrophils, and macrophages to IgG-induced anaphylaxis.79 Eicosanoids, lipid mediators generated from arachidonic acids, are also released from basophils upon stimulation. Basophils have

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

6

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

Fig. 4. Basophil-derived proteases induce infiltration of inflammatory cells. Basophils release serine proteases including mMCP-8 and mMCP-11 upon degranulation. mMCP-11 acts on serum proteins and proteolytic products of serum proteins induce the infiltration of other inflammatory cells in a GPCR-dependent manner. Of note, mMCP-11 induces the infiltration of basophils, leading to the further secretion of serine proteases from activated basophils. In contrast, mMCP-8 induces the up-regulation of chemokine production, possibly through acting on cells present in skin. Thus, basophil-derived serine proteases induce accumulation of inflammatory cells.

long been considered to release a much narrower range of eicosanoids, compared to mast cells.80 However, our recent study revealed that basophils can produce 5-lipoxygenase (5-LOX) metabolites and cyclooxygenase (COX) metabolites upon stimulation.81 Furthermore, the production of COX metabolites from mast cells and basophils are differentially regulated by COX-1 and COX-2, leading to the distinct time course of metabolite production, namely early-phase after stimulation in mast cells while late-phase after stimulation in basophils.81 Regulation of other immune cells by basophils Recent studies have revealed that basophils contribute to immune regulation through their interaction with other immune cells, including T cells, B cells, monocytes and macrophages.44 Basophils play a role in the regulation of acquired immunity, especially in the induction of Th2 differentiation39,49,82e84 and amplification of humoral memory responses.66,85 In addition, basophil-derived IL-4 is involved in the induction of M2-type macrophages, leading to the resolution of inflammation and protection immunity against parasites.12,18 In this section, we will focus on the immune modulatory functions of basophils. Regulation of T cells by basophils Th2 cells are crucial for protective immunity against extracellular parasites and in several allergic reactions.86 IL-4 is widely recognized to play critical roles in the differentiation of naïve T cells into Th2 cells. The cellular source of IL-4 responsible for initial Th2 differentiation has long been a matter of debate, because several cell types, including natural killer T cells, T cells, mast cells, eosinophils, and basophils, are known to be able to produce IL-4.

Basophils rapidly release large amounts of IL-4 in response to a variety of stimuli, as described in previous sections. Additionally, analyses using IL-4-green fluorescence protein (GFP) reporter mice revealed that basophils are the major source of IL-4 during helminth infections.87 Indeed, co-culture of naïve T cells with wildtype (WT) basophils in the presence of DCs induces robust production of IL-4 in T cells, while co-culture with IL-4-deficient basophils fails to do so.88,89 These results highlight the importance of basophils as a provider of IL-4 for Th2 differentiation in vitro. The role of basophils in Th2 differentiation through the provision of IL-4 was further supported in a Th2 differentiation model caused by allergenic proteases such as papain.49 Basophils were transiently recruited to draining lymph nodes 1 day before the peak of Th2 differentiation in response to subcutaneous injection of papain.49 Basophils were localized in the T cell zone of draining lymph nodes and expressed IL-4 in response to papain stimulation. Depletion of basophils abolished Th2 differentiation induced by papain immunization. Therefore, it was assumed that DCs act as antigen-presenting cells (APCs) to induce Th2 differentiation whereas basophils function as accessory cells in providing IL-4 to T cells (Fig. 5A). Following reports from three independent groups demonstrated, under different experimental conditions, that basophils, rather than DCs, function as the critical APCs in driving Th2 differentiation in distinct experimental conditions (Fig. 5B).82e84 In all settings, basophils expressed both major histocompatibility complex class II (MHC-II) and co-stimulatory molecules (CD80, CD86, or CD40) necessary for APC function and could process and present antigens to naïve T cells, leading to Th2 cell differentiation. Depletion of basophils using anti-FcεRI antibody abolished Th2 differentiation in vivo, whereas depletion of DCs using CD11c-DTR chimeric mice did not affect Th2 differentiation in these models.82,83

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

7

Fig. 5. Basophils play key roles in Th2 differentiation. A. Role of basophils as a provider of IL-4 necessary for Th2 differentiation. DCs serve as APCs to promote Th2 differentiation, and basophils in the vicinity of T cells supply IL-4 to T cells. B. Role of basophils as APCs producing IL-4. Basophils express MHC-II and function as crucial APCs for Th2 differentiation. C. Role of trogocytosis of peptide-MHC-II complexes from DCs to basophils. Basophils acquire peptide-MHC-II complexes from DCs in cell contact-dependent manner, and peptideMHC-II-dressed basophils function as APCs to drive Th2 differentiation.

Furthermore, mice in which MHC-II expression was restricted to DCs did not show Th2 differentiation in vivo.82,83 Conversely, adoptive transfer of antigen-pulsed basophils was found to be sufficient for the initiation of Th2 responses.83,84 This paradigm shift was greeted with great enthusiasm, but also with criticism.90 One concern has been the method used for depletion of DCs and basophils. A report suggested the possibility that radioresistant DCs may have remained intact in the DC-depleted chimeric mice.91 Another report argued that the basophil-depleting anti-FcεRI antibody may also have ablated FcεRI-expressing inflammatory DCs.92 Indeed, the crucial role of DCs in Th2 differentiation was demonstrated in studies that followed,14,93e95 suggesting that the relative contributions of basophils and DCs to Th2 differentiation vary depending on experimental conditions. Additionally, basophils show relatively low levels of cathepsin S expression, raising concerns about basophils' ability of process and present antigen.92 Thus, the significance of MHC-II expression on basophils and the antigen presentation capacity of basophils remain controversial. One recent report showed that basophils efficiently induce Th2 differentiation in response to peptide antigen rather than protein antigen.39 Basophils contribute to ovalbumin (OVA) peptideinduced Th2 differentiation, but not OVA protein-induced Th2 differentiation. Basophils have low capacity to take up and process antigens, and thus are unable to present antigens to T cells when protein antigens are administered. In contrast, basophils can induce T cell proliferation and Th2 differentiation when basophils and naïve T cells are co-cultured in the presence of peptide antigens. From these results, authors have concluded that properties of antigens, such as proteins, peptides, and haptens, may determine the relative contribution of basophils to Th2 differentiation.39 We hypothesized that the difference in the level of MHC-II expression on basophils might determine the contribution of basophils to Th2 differentiation, and investigated MHC-II expression on basophils in various experimental conditions.96 We clearly detected basophil MHC-II expression under certain conditions. Unexpectedly, MHC-II expression was detected only at the protein level, but not at the transcription level, suggesting that basophils acquire MHC-II molecules from MHC-II-expressing cells such as

DCs. Consistently, co-culture of basophils with DCs results in the detection of DC-derived peptide-MHC-II complexes on basophils. Transfer of peptide-MHC-II complexes from DCs to basophils was accompanied by the transfer of plasma membrane patches, suggesting the involvement of trogocytosis in this phenomenon.97,98 Trogocytosis of MHC-II from DCs to basophils appears to occur in vivo, because MHC-II expression on basophils isolated from draining lymph nodes was abolished in DC-specific MHC-II-deficient mice during atopic dermatitis-like inflammation. Acquired peptide-MHC-II complexes enable basophils to stimulate antigenspecific T cells and induce IL-4 production in T cells. Thus, basophils can function as Th2-driving APCs through trogocytosismediated MHC-II acquisition from DCs (Fig. 5C). The relative contribution of basophils to Th2 cell differentiation may depend on the extent of MHC-II trogocytosis from DCs. This appears to reconcile some discrepancies observed previous studies. Regulation of B cells by basophils Besides their roles in T cell differentiation, basophils have been shown to contribute to the modulation of B cell memory responses in mice and humans.66,85 Basophils produce large amounts of IL-4 in secondary immune responses after immunization.99 However, the role of basophil-derived IL-4 in memory responses, especially antibody production by B cells, has remained elusive until recently. Denzel et al. showed that basophils play crucial roles in humoral immune responses by producing IL-4 and IL-6, which induce a B cell helper phenotype in CD4þ T cells and enhance B cell proliferation and antibody production.66 Basophils can efficiently capture antigens after primary immunization via antigen-specific IgE and high-affinity IgE receptors on basophils.66,100 Basophils are the main source of IL-4 and IL-6 after challenge, as shown in previous studies. Of note, basophil depletion abrogated the production of antigen-specific IgG1 and IgG2a antibody after secondary antigen challenge. The number of antigen-specific B cells also decreased after depletion of basophils. Indeed, in vitro co-culture of activated WT basophils, but not IL-6-deficient basophils, with activated CD4 T cells and B cells enhanced the proliferation of and antibody

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

8

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

production by B cells, suggesting the importance of basophilderived IL-6 in B cell help. Additionally, activated basophils induce a B cell helper phenotype in CD4 T cells through IL-4, IL-6, and CD40L expression. Furthermore, Denzel et al. demonstrated the significance of basophils in a vaccination model using pneumococcal surface protein A (PspA), a component of Streptococcus pneumoniae. Basophil depletion decreased PspA-specific antibody production and increased the occurrence of sepsis caused by intratracheal infection with S. pneumoniae. Later studies revealed that basophils in mice and humans support plasma cell survival in the bone marrow and spleen and that this is partly dependent on IL-4 and IL-6 produced by basophils.101,102 In addition, long-term depletion of basophils after immunization reduced the number of plasma cells in spleens.101 Another group discovered a B cell-stimulating function of basophils in response to IgD.85 Circulating basophils in humans constitutively exhibit abundant surface IgD via unknown receptors on their cell surface. Crosslinking of IgD using anti-IgD monoclonal antibody induces calcium influx and the production of IL-4, IL-13, soluble B cell-activating factor (BAFF), and membrane-bound a proliferation-inducing ligand (APRIL), which are known to be B cellactivating factors. Indeed, co-culture of IgD-activated basophils with B cells induced the production of IgM, IgA, and IgG in vitro. Furthermore, IgD stimulation of basophils induced the expression of antimicrobial factors, including b-defensin 3 and cathelicidin. Because IgD secreted from plasmablasts in the upper respiratory mucosa reacts with respiratory bacteria, IgD-activated basophils appear to play crucial roles in innate and adaptive immune protection from pathogens by producing anti-bacterial factors and antibodies specific for pathogens. Activation of basophils contributes to the production of autoantibodies in a lupus-like nephritis model.103 Basophils are activated by IgE-immune complexes and support the production of autoreactive antibodies, leading to lupus-like nephritis. Furthermore, serum levels of autoreactive IgE antibody and the expression of activation markers on basophils are associated with disease activity in patients with systemic lupus erythematosus (SLE), suggesting the involvement of IgE and basophils in patients with SLE.103,104

Recent reports indicate that M2 macrophage generation induced by basophil-derived IL-4 plays key roles in a wide variety of immune responses. We showed that M2 macrophages generated in the skin are important for protection from the helminth Nippostrongylus brasiliensis (Nb). During secondary Nb infection, IgEarmed basophils infiltrate skin infection sites and trap Nb larvae in skin. Basophil-derived IL-4 promotes the generation of M2 macrophages, which leads to the retention and killing of larvae by arginase-1.18 Additionally, a recent report showed that M2 macrophage generation in response to basophil-derived IL-4 contributes to liver homeostasis after infection with Listeria monocytogenes (Lm). Lm infection induces early cell death of liver-resident Kupffer cells, resulting in anti-bacterial type 1 responses. Kupffer cell death also induces secretion of IL-33 from hepatocytes, leading to IL-4 production by basophils and M2 macrophage generation from monocytes. Differentiated M2 macrophages replace dead Kupffer cells to maintain tissue homeostasis.108 Concluding remarks Basophils have long been neglected in the immunology field because of their similarities with mast cells and their rarity. However, recent advances in the development of analytical tools have accelerated functional research on basophils. Basophils are now accepted to play key roles in various types of IgE-mediated allergic inflammation. Moreover, basophils have also been shown to play crucial roles in TSLP-mediated and IgE-independent allergic inflammation. Basophils have the potential to initiate and expand inflammation through the production of specific cytokines and proteases. Basophils can also induce Th2 differentiation in cooperation with DCs. In addition, basophils play significant roles in the resolution of inflammation by inducing M2 macrophages. Recent clinical experiences suggest the role of basophils in the pathogenesis of several allergic disorders. Therefore, further elucidation of the molecular mechanisms underlying basophilmediated allergic diseases will be the good help for the development of novel therapeutic target for allergic diseases. Acknowledgments

Regulation of monocytes and macrophages by basophils Our group discovered in an IgE-CAI model that basophil-derived IL-4 dampens exacerbated inflammation by inducing the differentiation of M2-like macrophages in later stages of inflammation (Fig. 3).12 Macrophages show phenotypic plasticity in response to various environmental stimuli such as classically activated M1 macrophages and alternatively activated M2 macrophages, which mirror Th1 and Th2 polarization in T cells, respectively.105,106 M2 macrophages are generally assumed to play significant roles in wound healing, tissue remodeling, parasite clearance, and resolution of excessive inflammation.105,106 However, the role of M2 macrophages in allergic inflammation remains controversial, because some studies have shown that M2 macrophages promote allergic responses, whereas others demonstrate suppressive effects on allergic inflammation.107 In IgE-CAI responses, inflammatory monocytes are recruited to skin lesions and differentiate into M2like macrophages in response to IL-4, which results in the suppression of excess inflammation in allergic reactions. Based on evidence that basophils are the major sources of IL-4 in skin lesions in IgE-CAI and that basophil depletion impairs the generation of M2-like macrophages, IL-4 secreted by activated basophils appears to contribute to M2-like macrophage polarization. Thus, basophilderived IL-4 involves the termination of IgE-CAI by promoting M2 macrophage generation.

This work is supported by research grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant number: 15H05786). Conflict of interest The authors have no conflict of interest to declare.

References 1. Galli SJ. Mast cells and basophils. Curr Opin Hematol 2000;7:32e9. 2. Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010;125:S73e80. 3. Sokol CL, Medzhitov R. Emerging functions of basophils in protective and allergic immune responses. Mucosal Immunol 2010;3:129e37. 4. Karasuyama H, Mukai K, Obata K, Tsujimura Y, Wada T. Nonredundant roles of basophils in immunity. Annu Rev Immunol 2011;29:45e69. 5. Voehringer D. Protective and pathological roles of mast cells and basophils. Nat Rev Immunol 2013;13:362e75. 6. Dwyer DF, Barrett NA, Austen KF, Immunological Genome Project C. Expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat Immunol 2016;17:878e87. 7. Koshino T, Arai Y, Miyamoto Y, Sano Y, Itami M, Teshima S, et al. Airway basophil and mast cell density in patients with bronchial asthma: relationship to bronchial hyperresponsiveness. J Asthma 1996;33:89e95. 8. Irani AM, Huang C, Xia HZ, Kepley C, Nafie A, Fouda ED, et al. Immunohistochemical detection of human basophils in late-phase skin reactions. J Allergy Clin Immunol 1998;101:354e62. 9. Ito Y, Satoh T, Takayama K, Miyagishi C, Walls AF, Yokozeki H. Basophil recruitment and activation in inflammatory skin diseases. Allergy 2011;66: 1107e13.

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10 10. Mukai K, Matsuoka K, Taya C, Suzuki H, Yokozeki H, Nishioka K, et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 2005;23: 191e202. 11. Obata K, Mukai K, Tsujimura Y, Ishiwata K, Kawano Y, Minegishi Y, et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 2007;110:913e20. 12. Egawa M, Mukai K, Yoshikawa S, Iki M, Mukaida N, Kawano Y, et al. Inflammatory monocytes recruited to allergic skin acquire an antiinflammatory M2 phenotype via basophil-derived interleukin-4. Immunity 2013;38:570e80. 13. Sawaguchi M, Tanaka S, Nakatani Y, Harada Y, Mukai K, Matsunaga Y, et al. Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness. J Immunol 2012;188:1809e18. 14. Ohnmacht C, Schwartz C, Panzer M, Schiedewitz I, Naumann R, Voehringer D. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010;33:364e74. 15. Hashimoto T, Satoh T, Yokozeki H. Protective role of STAT6 in basophildependent prurigo-like allergic skin inflammation. J Immunol 2015;194: 4631e40. 16. Cheng LE, Sullivan BM, Retana LE, Allen CD, Liang HE, Locksley RM. IgE-activated basophils regulate eosinophil tissue entry by modulating endothelial function. J Exp Med 2015;212:513e24. 17. Wada T, Ishiwata K, Koseki H, Ishikura T, Ugajin T, Ohnuma N, et al. Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks. J Clin Investig 2010;120:2867e75. 18. Obata-Ninomiya K, Ishiwata K, Tsutsui H, Nei Y, Yoshikawa S, Kawano Y, et al. The skin is an important bulwark of acquired immunity against intestinal helminths. J Exp Med 2013;210:2583e95. 19. Haenuki Y, Matsushita K, Futatsugi-Yumikura S, Ishii KJ, Kawagoe T, Imoto Y, et al. A critical role of IL-33 in experimental allergic rhinitis. J Allergy Clin Immunol 2012;130:184e94. e11. 20. Shiraishi Y, Jia Y, Domenico J, Joetham A, Karasuyama H, Takeda K, et al. Sequential engagement of FcepsilonRI on mast cells and basophil histamine H(4) receptor and FcepsilonRI in allergic rhinitis. J Immunol 2013;190: 539e48. 21. Miyahara S, Miyahara N, Takeda K, Joetham A, Gelfand EW. Physiologic assessment of allergic rhinitis in mice: role of the high-affinity IgE receptor (FcepsilonRI). J Allergy Clin Immunol 2005;116:1020e7. 22. Miyahara S, Miyahara N, Lucas JJ, Joetham A, Matsubara S, Ohnishi H, et al. Contribution of allergen-specific and nonspecific nasal responses to earlyphase and late-phase nasal responses. J Allergy Clin Immunol 2008;121: 718e24. 23. Wakahara K, Van VQ, Baba N, Begin P, Rubio M, Delespesse G, et al. Basophils are recruited to inflamed lungs and exacerbate memory Th2 responses in mice and humans. Allergy 2013;68:180e9. 24. Zhong W, Su W, Zhang Y, Liu Q, Wu J, Di C, et al. Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin-induced allergic airway inflammation. Immunology 2014;142:202e15. 25. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell FceRI expression and function. J Allergy Clin Immunol 2004;114:527e30. 26. Eckman JA, Sterba PM, Kelly D, Alexander V, Liu MC, Bochner BS, et al. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol 2010;125:889e95. e7. 27. Maurer M, Weller K, Bindslev-Jensen C, Gimenez-Arnau A, Bousquet PJ, Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report. Allergy 2011;66:317e30. 28. Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368:924e35. 29. Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Bulbul Baskan E, Bradley MS, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study. J Investig Dermatol 2015;135:67e75. 30. Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol 2008;20:709e16. 31. Saini SS, Omachi TA, Trzaskoma B, Hulter HN, Rosen K, Sterba PM, et al. Effect of omalizumab on blood basophil counts in patients with chronic idiopathic/ spontaneous urticaria. J Investig Dermatol 2017;137:958e61. 32. Eckman JA, Hamilton RG, Gober LM, Sterba PM, Saini SS. Basophil phenotypes in chronic idiopathic urticaria in relation to disease activity and autoantibodies. J Investig Dermatol 2008;128:1956e63. 33. Sterba PM, Hamilton RG, Saini SS. Suppression of basophil FcvarepsilonRI activation by serum from active chronic idiopathic/spontaneous urticaria (CIU/CSU) subjects. J Investig Dermatol 2015;135:1454e6. 34. Hill DA, Siracusa MC, Ruymann KR, Tait Wojno ED, Artis D, Spergel JM. Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children. Allergy 2014;69:674e7. 35. Campo P, Rondon C, Gould HJ, Barrionuevo E, Gevaert P, Blanca M. Local IgE in non-allergic rhinitis. Clin Exp Allergy 2015;45:872e81. 36. Motomura Y, Morita H, Moro K, Nakae S, Artis D, Endo TA, et al. Basophilderived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 2014;40:758e71.

9

37. Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 2012;18:538e46. 38. Nakashima C, Otsuka A, Kitoh A, Honda T, Egawa G, Nakajima S, et al. Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis. J Allergy Clin Immunol 2014;134:100e7. 39. Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A, et al. Basophils are required for the induction of Th2 immunity to haptens and peptide antigens. Nat Commun 2013;4:1739. 40. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 2014;133:1390e9. 9 e1-6. 41. Kim BS, Wang K, Siracusa MC, Saenz SA, Brestoff JR, Monticelli LA, et al. Basophils promote innate lymphoid cell responses in inflamed skin. J Immunol 2014;193:3717e25. 42. Noti M, Wojno ED, Kim BS, Siracusa MC, Giacomin PR, Nair MG, et al. Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med 2013;19:1005e13. 43. Venturelli N, Lexmond WS, Ohsaki A, Nurko S, Karasuyama H, Fiebiger E, et al. Allergic skin sensitization promotes eosinophilic esophagitis through the IL33-basophil axis in mice. J Allergy Clin Immunol 2016;138:1367e80. e5. 44. Yamanishi Y, Karasuyama H. Basophil-derived IL-4 plays versatile roles in immunity. Semin Immunopathol 2016;38:615e22. 45. Hida S, Yamasaki S, Sakamoto Y, Takamoto M, Obata K, Takai T, et al. Fc receptor g-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nat Immunol 2009;10:214e22. 46. Kroeger KM, Sullivan BM, Locksley RM. IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol 2009;86:769e78. 47. Yoshimoto T, Nakanishi K. Roles of IL-18 in basophils and mast cells. Allergol Int 2006;55:105e13. 48. Kamijo S, Nunomura S, Ra C, Kanaguchi Y, Suzuki Y, Ogawa H, et al. Innate basophil IL-4 responses against allergens, endotoxin, and cytokines require the Fc receptor gamma-chain. J Allergy Clin Immunol 2016;137: 1613e5. e2. 49. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 2008;9:310e8. 50. Rosenstein RK, Bezbradica JS, Yu S, Medzhitov R. Signaling pathways activated by a protease allergen in basophils. Proc Natl Acad Sci U S A 2014;111: E4963e71. 51. Tsai SH, Kinoshita M, Kusu T, Kayama H, Okumura R, Ikeda K, et al. The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells. Immunity 2015;42:279e93. 52. Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 2011;477:229e33. 53. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673e80. 54. Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, et al. Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol 2010;125:1403e7. e4. 55. Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202:541e9. 56. Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A 2006;103: 11736e41. 57. Leyva-Castillo JM, Hener P, Jiang H, Li M. TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J Investig Dermatol 2013;133:154e63. 58. Sherrill JD, Gao PS, Stucke EM, Blanchard C, Collins MH, Putnam PE, et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol 2010;126:160e5. e3. 59. Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet 2010;42:289e91. 60. Muto T, Fukuoka A, Kabashima K, Ziegler SF, Nakanishi K, Matsushita K, et al. The role of basophils and proallergic cytokines, TSLP and IL-33, in cutaneously sensitized food allergy. Int Immunol 2014;26:539e49. 61. Han H, Thelen TD, Comeau MR, Ziegler SF. Thymic stromal lymphopoietinmediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis. J Clin Investig 2014;124:5442e52. 62. Borriello F, Granata F, Marone G. Basophils and skin disorders. J Investig Dermatol 2014;134:1202e10. 63. Siracusa MC, Kim BS, Spergel JM, Artis D. Basophils and allergic inflammation. J Allergy Clin Immunol 2013;132:789e801. quiz 788. 64. Schroeder JT. Basophils: emerging roles in the pathogenesis of allergic disease. Immunol Rev 2011;242:144e60. 65. Yuk CM, Park HJ, Kwon BI, Lah SJ, Chang J, Kim JY, et al. Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity. Sci Rep 2017;7: 41744.

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007

10

K. Miyake, H. Karasuyama / Allergology International xxx (2017) 1e10

66. Denzel A, Maus UA, Rodriguez Gomez M, Moll C, Niedermeier M, Winter C, et al. Basophils enhance immunological memory responses. Nat Immunol 2008;9:733e42. 67. Sektioglu IM, Carretero R, Bulbuc N, Bald T, Tuting T, Rudensky AY, et al. Basophils promote tumor rejection via chemotaxis and infiltration of CD8þ T cells. Cancer Res 2017;77:291e302. 68. Qi Y, Operario DJ, Oberholzer CM, Kobie JJ, Looney RJ, Georas SN, et al. Human basophils express amphiregulin in response to T cell-derived IL-3. J Allergy Clin Immunol 2010;126:1260e6. e4. 69. Meulenbroeks C, van Weelden H, Schwartz C, Voehringer D, Redegeld FA, Rutten VP, et al. Basophil-derived amphiregulin is essential for UVB irradiation-induced immune suppression. J Investig Dermatol 2015;135: 222e8. 70. Ugajin T, Kojima T, Mukai K, Obata K, Kawano Y, Minegishi Y, et al. Basophils preferentially express mouse Mast Cell Protease 11 among the mast cell tryptase family in contrast to mast cells. J Leukoc Biol 2009;86:1417e25. 71. Poorafshar M, Helmby H, Troye-Blomberg M, Hellman L. MMCP-8, the first lineage-specific differentiation marker for mouse basophils. Elevated numbers of potent IL-4-producing and MMCP-8-positive cells in spleens of malaria-infected mice. Eur J Immunol 2000;30:2660e8. 72. Iki M, Tanaka K, Deki H, Fujimaki M, Sato S, Yoshikawa S, et al. Basophil tryptase mMCP-11 plays a crucial role in IgE-mediated, delayed-onset allergic inflammation in mice. Blood 2016;128:2909e18. 73. Yamagishi H, Mochizuki Y, Hamakubo T, Obata K, Ugajin T, Sato S, et al. Basophil-derived mouse mast cell protease 11 induces microvascular leakage and tissue edema in a mast cell-independent manner. Biochem Biophys Res Commun 2011;415:709e13. 74. Tsutsui H, Yamanishi Y, Ohtsuka H, Sato S, Yoshikawa S, Karasuyama H. The basophil-specific protease mMCP-8 provokes an inflammatory response in the skin with microvascular hyperpermeability and leukocyte infiltration. J Biol Chem 2017;292:1061e7. 75. MacGlashan Jr DW. Basophil activation testing. J Allergy Clin Immunol 2013;132:777e87. 76. Tsujimura Y, Obata K, Mukai K, Shindou H, Yoshida M, Nishikado H, et al. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity 2008;28: 581e9. 77. Jonsson F, Mancardi DA, Kita Y, Karasuyama H, Iannascoli B, Van Rooijen N, et al. Mouse and human neutrophils induce anaphylaxis. J Clin Investig 2011;121:1484e96. 78. Jiao D, Liu Y, Lu X, Liu B, Pan Q, Liu Y, et al. Macrophages are the dominant effector cells responsible for IgG-mediated passive systemic anaphylaxis challenged by natural protein antigen in BALB/c and C57BL/6 mice. Cell Immunol 2014;289:97e105. 79. Beutier H, Gillis CM, Iannascoli B, Godon O, England P, Sibilano R, et al. IgG subclasses determine pathways of anaphylaxis in mice. J Allergy Clin Immunol 2017;139:269e80. e7. 80. Warner JA, Peters SP, Lichtenstein LM, Hubbard W, Yancey KB, Stevenson HC, et al. Differential release of mediators from human basophils: differences in arachidonic acid metabolism following activation by unrelated stimuli. J Leukoc Biol 1989;45:558e71. 81. Bando T, Fujita S, Nagano N, Yoshikawa S, Yamanishi Y, Minami M, et al. Differential usage of COX-1 and COX-2 in prostaglandin production by mast cells and basophils. Biochem Biophys Rep 2017;10:82e7. 82. Perrigoue JG, Saenz SA, Siracusa MC, Allenspach EJ, Taylor BC, Giacomin PR, et al. MHC class IIedependent basophileCD4þ T cell interactions promote TH2 cytokineedependent immunity. Nat Immunol 2009;10:697e705. 83. Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 2009;10:713e20. 84. Yoshimoto T, Yasuda K, Tanaka H, Nakahira M, Imai Y, Fujimori Y, et al. Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4þ T cells. Nat Immunol 2009;10:706e12. 85. Chen K, Xu W, Wilson M, He B, Miller NW, Bengten E, et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial,

86. 87.

88.

89.

90. 91.

92.

93.

94.

95.

96.

97. 98.

99.

100. 101. 102. 103.

104.

105. 106. 107. 108.

proinflammatory and B cell-stimulating programs in basophils. Nat Immunol 2009;10:889e98. Paul WE, Zhu J. How are TH2-type immune responses initiated and amplified? Nat Rev Immunol 2010;10:225e35. Min B, Prout M, Hu-Li J, Zhu J, Jankovic D, Morgan ES, et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med 2004;200:507e17. Hida S, Tadachi M, Saito T, Taki S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 2005;106: 2011e7. Oh K, Shen T, Le Gros G, Min B. Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils. Blood 2007;109: 2921e7. Duriancik DM, Hoag KA. Mistaken identity: purified basophils likely contaminated with dendritic cells. Cytometry A 2014;85:570e2. Tang H, Cao W, Kasturi SP, Ravindran R, Nakaya HI, Kundu K, et al. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 2010;11:608e17. Hammad H, Plantinga M, Deswarte K, Pouliot P, Willart MA, Kool M, et al. Inflammatory dendritic cellsenot basophilseare necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 2010;207:2097e111. Phythian-Adams AT, Cook PC, Lundie RJ, Jones LH, Smith KA, Barr TA, et al. CD11c depletion severely disrupts Th2 induction and development in vivo. J Exp Med 2010;207:2089e96. Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A. CD301b(þ) dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 2013;39:733e43. Plantinga M, Guilliams M, Vanheerswynghels M, Deswarte K, BrancoMadeira F, Toussaint W, et al. Conventional and monocyte-derived CD11b(þ) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 2013;38:322e35. Miyake K, Shiozawa N, Nagao T, Yoshikawa S, Yamanishi Y, Karasuyama H. Trogocytosis of peptide-MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils. Proc Natl Acad Sci U S A 2017;114: 1111e6. Joly E, Hudrisier D. What is trogocytosis and what is its purpose? Nat Immunol 2003;4:815. Campana S, De Pasquale C, Carrega P, Ferlazzo G, Bonaccorsi I. Cross-dressing: an alternative mechanism for antigen presentation. Immunol Lett 2015;168: 349e54. Khodoun MV, Orekhova T, Potter C, Morris S, Finkelman FD. Basophils initiate IL-4 production during a memory T-dependent response. J Exp Med 2004;200: 857e70. Mack M, Schneider MA, Moll C, Cihak J, Bruhl H, Ellwart JW, et al. Identification of antigen-capturing cells as basophils. J Immunol 2005;174:735e41. Gomez MR, Talke Y, Goebel N, Hermann F, Reich B, Mack M. Basophils support the survival of plasma cells in mice. J Immunol 2010;185:7180e5. Dijkstra D, Meyer-Bahlburg A. Human basophils modulate plasma cell differentiation and maturation. J Immunol 2017;198:229e38. Charles N, Hardwick D, Daugas E, Illei GG, Rivera J. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med 2010;16:701e7. Dema B, Charles N, Pellefigues C, Ricks TK, Suzuki R, Jiang C, et al. Immunoglobulin E plays an immunoregulatory role in lupus. J Exp Med 2014;211: 2159e68. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013;229:176e85. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6:13. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011;11:723e37. riot C, Dupuis T, Jouvion G, Eberl G, Disson O, Lecuit M. Liver-resident Ble macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 2015;42:145e58.

Please cite this article in press as: Miyake K, Karasuyama H, Emerging roles of basophils in allergic inflammation, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.04.007