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Roles and Regulation of Gastrointestinal Eosinophils in and Disease YunJae Jung and Marc E. Rothenberg This information is current as J Immunol 2014; 193:999-1005; ; of September 29, 2021. doi: 10.4049/jimmunol.1400413 http://www.jimmunol.org/content/193/3/999 Downloaded from References This article cites 88 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/193/3/999.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Roles and Regulation of Gastrointestinal Eosinophils in Immunity and Disease YunJae Jung*,† and Marc E. Rothenberg* Eosinophils have historically been considered to be de- using eosinophil-specific surface markers was established (5). structive end-stage effector cells that have a role in Additionally, the development of eosinophil-deficient mouse parasitic and allergic reactions by the release strains has expanded the understanding of the role of intes- of their -derived cytotoxic proteins. However, an tinal eosinophils from dogmatic antiparasitic effector cells to increasing number of experimental observations indi- immune modulatory cells. In this article, we discuss emerg- cate that eosinophils also are multifunctional leukocytes ing advances in the understanding of intestinal eosino- involved in diverse inflammatory and physiologic immune phils at baseline and during inflammatory gastrointestinal responses. Under homeostatic conditions, eosinophils disorders, including primary gastrointestinal dis- Downloaded from are particularly abundant in the of orders (EGIDs), such as eosinophilic (EoE) (6). the , where their involvement in Developmental properties of eosinophils various biological processes within the gastrointestinal tract has been posited. In this review, we summarize the Eosinophils develop in the from pluripotent molecular steps involved in eosinophil development and stem cells that become eosinophil progenitors marked by + + http://www.jimmunol.org/ describe eosinophil trafficking to the gastrointestinal CD34 CD125 expression. Eosinophil lineage specification is tract. We synthesize the current findings on the pheno- determined by the interplay of several transcription factors, typic and functional properties of gastrointestinal eo- including the zinc finger transcription factor GATA-binding protein 1 (GATA-1), the E26 transformation-specific family sinophils and the accumulating evidence that they member PU.1, IFN consensus sequence binding protein, and have a contributory role in gastrointestinal disorders, C/EBP family members (2, 7, 8), as well as by regulation by with a focus on primary eosinophilic gastrointestinal dis- microRNAs, including miR-21 and miR-223 (9, 10). Of the orders. Finally, we discuss the potential role of eosino- transcription factors, GATA-1 is the most important; targeted

phils as modulators of the intestinal . deletion of the high-affinity double palindromic GATA-1 by guest on September 29, 2021 The Journal of Immunology, 2014, 193: 999–1005. binding site in the Gata1 promoter results in eosinophil- depleted mice, referred to as ΔdblGATA mice (11). ΔdblGATA osinophils are multifunctional proinflammatory leu- mice, along with another eosinophil-deficient strain gener- kocytes involved in the of allergic dis- ated using a promoter of the gene to E orders and are implicated in the protection against drive expression of cytocidal diphtheria A (referred to helminth infections (1, 2). Eosinophils are generally thought as PHIL mice) (12), are being used to uncover the function of as proinflammatory cells because they release pleotropic of eosinophils (13). Eosinophil development is guided by , , and lipid mediators, as well as toxic signals from the aforementioned transcription factors; sub- cytoplasmic granule constituents, including major basic pro- sequently, permissive proliferation and differentiation are tein, eosinophil cationic protein, eosinophil peroxidase, and regulated primarily by IL-5, although IL-3 and GM-CSF can eosinophil-derived neurotoxin (EDN) (3, 4). Although - also contribute (2). Of these cytokines, IL-5 is the most ophils are recognized as circulating cells, composing 1–5% specific for selective differentiation of eosinophils, stimulat- of peripheral leukocytes, they are primarily resident in ing their migration from the bone marrow to the circula- the lamina propria of the small intestine, where they com- tion (2, 14). Eosinophils released into the blood migrate into pose a substantial fraction (e.g., 20–30%) of the cellular the , , , and the gastrointes- population (2, 5). Recently, a standard protocol for the isola- tinal tract, with the last having the highest eosinophil levels tion of murine eosinophils from the intestinal lamina propria under homeostatic conditions (2). Levels of gastrointestinal

*Division of and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati College of Medicine, 3333 Burnet Avenue, ML7028, Cincinnati, OH University of Cincinnati College of Medicine, Cincinnati, OH 45229; and †Department 45229. E-mail address: [email protected] of Microbiology, Graduate School of Medicine, Gachon University, Incheon 406–799, Abbreviations used in this article: APRIL, a proliferation-inducing ligand; EDN, Republic of Korea eosinophil-derived neurotoxin; EGID, eosinophilic gastrointestinal disorder; EoE, eo- Received for publication February 12, 2014. Accepted for publication April 23, 2014. sinophilic esophagitis; GATA-1, GATA-binding protein 1; IBD, inflammatory bowel disease; ILC2, type 2 innate lymphoid ; PIR, paired Ig-like receptor; Siglec, sialic This work was supported by National Institutes of Health Grants U19 AI066738, R37 acid–binding Ig-like lectin; SIRP-a, signal regulatory protein a. A1045898, and U19 AI070235 and by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education Ó (2013R1A1A2004820). Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Dr. Marc E. Rothenberg, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400413 1000 BRIEF REVIEWS: GASTROINTESTINAL EOSINOPHILS eosinophils were estimated to be $10-fold higher than in steady-state but are ready for conversion to proinflammatory the circulation (2, 3). Examination of the entire gastrointes- cells via downregulation of CD22. tinal tract reveals that only the is devoid of baseline Under homeostatic conditions, most eosinophils produced eosinophils and that eosinophil levels progressively increase in the bone marrow migrate to the small intestine; this pro- from the stomach to the colon, where they can be fairly high cess is regulated by eosinophil expression of CCR3 and a4b7 (i.e., as many as 50 eosinophils/high-power microscopic field integrin because their cognate ligands (eotaxin and mucosal [4003]) (15). vascular addressin cell adhesion molecule 1, respectively) are constitutively expressed in the intestine (15, 26). b7 integrin Unique characteristics of intestinal eosinophils appears to be particularly important in the large intestine, Until recently, no detailed phenotypic analysis of intestinal whereas eotaxins mediate eosinophil homing in the large and eosinophils had been performed because of the difficulties small intestine of mice (26, 27). Gastrointestinal eosinophils inherent in identifying and/or isolating sufficient numbers of are postmitotic and have limited survival in the absence of these cells from the gastrointestinal tract. However, phenotypic survival-promoting signals (28); conversely, cytokine characterization of murine eosinophils in the intestinal lamina signaling through the common g-chain increases the lifespan propria was reported recently by several groups (5, 16, 17). For of murine small intestinal eosinophils (Fig. 1A) (5). There- detection of eosinophils in mice, there are several available fore, in combination with a specialized influx mechanism, the markers, including CCR3, sialic acid–binding Ig-like lectin prolonged survival of eosinophils ($14 d) contributes to their (Siglec)-F (homolog of siglec-8 in humans), and CD125, predominance in the gastrointestinal tract (5). In addition, Downloaded from which encodes for IL-5Ra (18–20). Although these markers signal regulatory protein a (SIRP-a), highly expressed in are primarily expressed on eosinophils, CCR3 also is expressed small intestinal eosinophils, inhibits of eosino- on mast cells and Th2 cells (21), Siglec-F is detected on al- phils by interaction with their ligand CD47, thus promoting veolar (22), and IL-5Ra is also expressed on eosinophil survival (Fig. 1A) (16). Also, type 2 innate lym- peritoneal B-1 cells (20). Therefore, none of these markers can phoid cells () have been identified as a specialized cell be considered to represent a definitive specificity for eosino- population supporting the maintenance of murine intestinal http://www.jimmunol.org/ phils. However, because eosinophils contain a dense concen- eosinophils by secreting IL-5 and IL-13, which promote eo- tration of cytoplasmic granules, their side scatter patterns sinophil survival and recruitment to the small intestine, re- under flow cytometry are readily distinguishable from those of spectively, via upregulation of eotaxin (29). Notably, the other lineages. Thus, a combination of the relative expression coexpression of IL-5 and IL-13 by ILC2s is enhanced after of CCR3, Siglec-F, and/or IL-5Ra with their side scatter caloric intake and regulated by vasoactive intestinal peptide, patterns can be used to delineate eosinophil subsets in the which stimulates ILC2s through vasoactive intestinal peptide intestine (Fig. 1A) (5, 16, 17). In addition to these markers, receptor type 2 to release IL-5 via a circadian rhythm (Fig. intestinal eosinophils of mice express higher levels of myeloid 1A) (29). However, under nutrient deprivation, ILC2s and by guest on September 29, 2021 marker CD11b than do their blood counterparts and are ILC2–derived IL-5 and IL-13 are also increased in the gut positive for CD11c, a surface marker used to identify intes- (30), thus suggesting complex interactions between eosinophil tinal dendritic cells (Fig. 1A) (5). Meanwhile, small intestinal survival and intestinal nutritional conditions. eosinophils isolated from mice are negative for other markers associated with intestinal dendritic cells, such as MHC class Migratory properties of intestinal eosinophils II, CD80, CD103, and CD205 (DEC-205) (5). Considering Most eosinophils generated in the bone marrow migrate to all that CD11c expression also occurs on murine eosinophils in segments of the gastrointestinal tract, with the exception of the the thymus and uterus, but not in the blood (5), it seems esophagus, coming to reside in the intestinal lamina propria plausible that it is affected by the local microenvironment under baseline conditions (2). Prenatal mice have comparable rather than being indicative of their Ag-presenting capacity. numbers of eosinophils in the gastrointestinal tract as do adult Along with CD11c, Siglec-F expression also is observed at mice; thus, at least relative to other leukocytes, eosinophil higher levels in eosinophils of the small intestine (5). It homing to the gastrointestinal tract seems to be independent remains to be determined whether the relative expressions of of the enteric flora (15), likely mediated by constitutive ILC2 CD11c and Siglec-F in murine eosinophils from different and eotaxin-1 (29). The recruitment of murine eosinophils to sources correlate with their functional differences in specific the gastrointestinal tract under the steady-state is regulated tissues. CD22, a –specific Siglec belonging to the in- primarily by eotaxin-1, which is localized in Ly6chighCCR2+ hibitory receptor family, is highly expressed on the surface of F4/80+CD11b+ cells that are under the regulation of calpro- murine, small intestinal eosinophils but is undetectable on tectin (S100a8/S100a9) (31, 32). The importance of eotaxin-1 eosinophils from the blood (Fig. 1A) (17). Because the small in regulating the baseline level of eosinophils in the gastro- intestine is a milieu rich in substances that stimulate eosino- intestinal tract is underscored by the severe deficiency in phils (23–25), CD22’s abundant expression on intestinal eosinophils in the intestinal mucosa, without any significant eosinophils might prevent overactivation of intestinal eosi- decrease in bone marrow and peripheral blood eosinophils, in nophils under homeostatic conditions. Notably, CD22 ex- eotaxin-1–deficient mice (15, 33). By genomic analyses, two pression on small intestinal eosinophils is decreased under additional chemokines, designated eotaxin-2 and eotaxin-3, various inflammatory conditions, such as bacterial coloniza- were identified on the basis of their eosinophil-selective che- tion, systemic IL-5 overexpression, and OVA-induced gas- moattractant activity (2). The specific activity of the eotaxin trointestinal inflammation (17). Therefore, it can be posited subfamily of chemokines is mediated by the G protein–coupled that small intestinal eosinophils receive negative-feedback receptor CCR3, which is primarily expressed on eosinophils signals from highly expressed inhibitory CD22 under the (Fig. 1A) (34, 35). Accordingly, deficiency in gastrointestinal The Journal of Immunology 1001 Downloaded from http://www.jimmunol.org/

FIGURE 1. Phenotypic and functional properties of gastrointestinal eosinophils. (A) In healthy conditions, eosinophils develop in the bone marrow and migrate to the lamina propria of gastrointestinal tract by a process regulated by CCR3/eotaxin-1. IL-5 secreted by ILC2s and cytokine signaling through the gc-chain receptors increase the lifespan of small intestinal eosinophils. Coexpression of IL-5 and IL-13 by ILC2s is enhanced by nutrient uptake, VIP stimulation, and IL-33. Eosinophil SIRP-a inhibits degranulation by interaction with membranous protein CD47, thus promoting eosinophil survival. IL-5 and eotaxin signaling is regulated by the opposing actions of PIR-A and PIR-B. (B) Eosinophils express a broad range of pattern-recognition receptors (PRR) and FcgR, allowing them to be stimulated by various pathogens, including bacteria, virus, and Ab-coated pathogens, such as helminths. Cytoplasmic granules and eosinophilic mitochondrial by guest on September 29, 2021 DNA secreted by gastrointestinal eosinophils mediate tissue pathology and participate in host clearance of pathogens. Eosinophils stimulated by Th2-type cytokines and -derived IL-33 mediate tissue inflammation in a variety of primary EGIDs. Eosinophils may also modulate –mediated immune responses, IgA class switching, and glucose homeostasis. eosinophils in mice, with the targeted deletion of CCR3, (2, 26). These integrins have prominent roles in eosino- supports the critical role of eotaxin-1 in the maintenance of phil trafficking during inflammation rather than during ho- intestinal eosinophils under homeostatic conditions (36). meostasis, as demonstrated by the reduced number of small Although eotaxin-1 is the major required for the intestinal eosinophils after oral stimulation in b7 baseline level of eosinophils in the gastrointestinal tract, gene–targeted mice compared with nondeficient mice (26). eotaxin-1 alone is unlikely to be sufficient, as it is abundantly Furthermore, in b7-deficient mice, eosinophil accumulation expressed in the upper gastrointestinal segments (e.g., tongue, in the small intestine after Trichinella spiralis is esophagus), and eosinophils are not normally present in these delayed compared with nondeficient mice (39). The traffick- locations (15). Paired Ig-like receptor (PIR)-B, which is highly ing of eosinophils to inflammatory sites also involves a number expressed in eosinophils and can suppress eotaxin/CCR3- cytokines, particularly those of the Th2 type, such as IL-4, IL- mediated eosinophil migration to the small intestine, may 5, and IL-13, of which only IL-5 is implicated in selective be an inhibitory checkpoint for esophageal eosinophil traf- tissue distribution (2). Under baseline conditions, eosinophils ficking (Fig. 1A) (37). Although it inhibits eosinophil mi- in the Peyer’s patch are barely detected in mice; however, after gration, PIR-B supports IL-5–induced expansion of murine IL-5 overexpression, they substantially localize to the inter- eosinophils by suppressing PIR-A–induced of bone follicular regions via eotaxin-1– and IL-5–dependent mecha- marrow eosinophils (38). nisms (40). Eosinophils also express a number of adhesion molecules involved in cell trafficking, including integrin a4b7, integrin Functional characteristics of intestinal eosinophils a4b1 (VLA-4), and the b2-integrin family (the CD18 fam- Eosinophils have long been considered effector cells that have ily) (2, 26). Integrin a4b1 interacts with the endothelium via a protective role against parasitic helminth infection. However, VCAM-1 and fibronectin, the CD18 family of molecules eosinophils also are associated with numerous gastrointesti- binds to ICAM-1, and a4b7 integrin interacts with the mu- nal disorders, such as EoE, eosinophilic gastritis, eosinophilic cosal vascular addressin cell adhesion molecule 1 that is , and eosinophilic colitis, which are collectively re- expressed by the vascular endothelium in the intestinal tract ferred to as EGIDs, as well as inflammatory bowel diseases 1002 BRIEF REVIEWS: GASTROINTESTINAL EOSINOPHILS

(IBDs) (6). In contrast, numerous lines of evidence indicate eosinophil-derived mitochondrial DNA binds and kills bac- that eosinophils are multifunctional leukocytes involved in teria in the extracellular matrix of the mice intestine (54). germane biologic processes in the gastrointestinal tract. Here- Considering the abundant numbers of eosinophils in the after, the functional features of eosinophils as effector cells intestinal lamina propria, trapping bacteria with the DNA against pathogenic infections, as pathologic players in EGIDs complexes of eosinophils (mitochondrial DNA nets) could be and IBDs, and as modulators of gastrointestinal immune re- a highly effective mechanism for protecting the gastrointes- sponses, are discussed. tinal tract against pathogenic bacterial invasion.

Beneficial role of eosinophils Nonbeneficial role of eosinophils in gastrointestinal disorders: primary The antiparasitic functionality of eosinophils is based primarily EGID and IBD on their increase in the circulation and affected tissues during The most common primary EGID, EoE, is a worldwide helminth infections (41), as well as their ability to mediate in emerging disease representing the second most common vitro Ab-dependent cellular toxicity against helminthes (42, cause of chronic esophagitis (55, 56). Although infiltration of 43). Murine models of parasitic infection demonstrated eo- eosinophils into the esophageal mucosa is the hallmark of sinophil recruitment to infected tissues and parasite death EoE, accumulation of activated immune cells, such as mast mediated by the release of toxic cytoplasmic granules, such as cells, B cells, and T cells, as well as APCs, is also observed in (Fig. 1B) (44). Indeed, impaired resis- active EoE (56, 57). Along with inflammatory cell infiltration, tance against secondary infection with intestinal Nippos- hyperplasia of esophageal epithelial cells is a general histologic Downloaded from trongylus brasiliensis is observed in ΔdblGATA mice (45). characteristic of EoE (58). Although not fully understood, However, Schistosoma mansoni–infected ΔdblGATA and PHIL immune sensitization to a variety of foods and Th2-polarized mice have normal disease progression, despite the recruitment allergic inflammation in the esophageal mucosa have been of large numbers of eosinophils in the affected liver (46). In posited as the critical immunologic aspects of EoE develop- Trichinella spiralis–infected ΔdblGATA mice, the marked ment (57). In the absence of eosinophils, disease features, such death of T. spiralis muscle larvae by inducible NO synthase– as tissue remodeling (e.g., epithelial hyperplasia), collagen http://www.jimmunol.org/ producing and macrophages is observed, and accumulation, and gastric motility, are attenuated, implicat- excessive host inflammatory responses are linked to pathologic ing eosinophils as key effector cells, at least in these animal changes in infected muscle (47). Because transfer of eosino- models (59, 60). Eosinophil-derived TGF-b is implicated in phils into ΔdblGATA mice restores larvae survival, eosino- tissue remodeling of EoE and induces expression of periostin, phils have been paradoxically implicated in parasite survival, an extracellular matrix protein that increases eosinophil in- specifically through the promotion of Th2 cell recruitment filtration in the mucosal layer in patient biopsies, thus further and the prevention of - and -induced promoting disease pathogenesis (56, 61). Genetic suscepti- parasite death (47). Collectively, these data suggest that, un- bility in humans is linked to sequence variants at genetic by guest on September 29, 2021 der some conditions, there may be a symbiotic association locus 5q22 (encoding thymic stromal lymphopoietin), CRLF2 between gastrointestinal eosinophils and parasites that could (the thymic stromal lymphopoietin receptor), FLG (filaggrin), contribute to the maintenance of tissue homeostasis by and CCL26 (eotaxin-3), consistent with the complex interplay allowing parasites to reside in the host tissues with limited of epithelial cell gene products and Th2 immunity (62–64). consequences of such infection. Accordingly, we conclude Indeed, the Th2 cytokines IL-4, IL-5, and IL-13 are elevated that the eosinophil response to parasitic infection may vary by in the esophageal mucosa, with IL-13 having a particularly both helminth species and the specific tissue infected. Al- important role in EoE pathogenesis (Fig. 1B) (56). IL-13 though murine models provide an opportunity to delineate drives marked upregulation of eotaxin-3, thus promoting the role of the eosinophil in parasite infection, it is important the chemoattraction of CCR3+ eosinophils; further, IL-13 to point out that murine eosinophils are less effective than rat induces an EoE-like transcriptome in primary esophageal eosinophils in killing schistosomes (48) and do not bind IgE, epithelial cell cultures (65) and triggers production of peri- which may be an effector mechanism for human eosinophils ostin in primary esophageal cultures (61). Impaired barrier against parasites (49). Additionally, experimental infection function of the esophageal epithelium also was indicated as with parasites in mice is unlikely to adequately mimic natural a potential pathophysiological mechanism, as verified, at least infections in human. Therefore, cautious interpretation of the in part, by the decrease in desmosomal cadherin desmoglein murine results is warranted. Eosinophils express a broad range 1, an ICAM, in active EoE (66, 67). In fact, downregulation of pattern-recognition receptors, which supports their po- of desmoglein 1 by IL-13 not only induces impaired barrier tential role in responses against viral and bacterial infections function of the esophageal epithelium, it also initiates a (50). RNA viruses, such as respiratory syncytial virus, are proallergic transcriptional response, including POSTN (peri- susceptible to the antiviral activities of eosinophils, particu- ostin) expression (67). Considering that periostin can directly larly those mediated by eosinophil granule ribonucleases (e.g., enhance eosinophil adhesion, the decreased expression of eosinophil cationic protein and EDN) (51). IL-5–transgenic desmoglein 1 may further potentiate the inflammatory re- mice have improved clearance of Pseudomonas aeruginosa (52); sponse of EoE by increasing migration of eosinophils. however, it is possible that IL-5 mediates antibacterial effects IBDs are characterized by chronic inflammation of the in- independently of eosinophils (53). Even so, a previously testine, and elevated levels of eosinophils have been observed in unrecognized antibacterial function of eosinophils was dem- IBDs that correlate with disease severity (68, 69). Murine onstrated that involves eosinophils releasing their mitochon- models of IBD have provided important insights about the role drial DNA in response to LPS from Gram-negative bacteria of eosinophils in their pathogenesis. Increased numbers and (Fig. 1B) (54). Together with granule proteins, the secreted degranulation of eosinophils are observed in chemical-induced The Journal of Immunology 1003 models of IBD, and they are attenuated in eosinophil-deficient IgA class switching in this location (Fig. 1B). In the healthy mice and eotaxin-1–deficient mice, which exhibit reduced state, eosinophils are barely present in the Peyer’s patch or clinical scores and pathology (70, 71). Progression of colonic mesenteric lymph nodes (40), where T cell–dependent IgA inflammation is also attenuated with depletion of eosinophils class switching takes place. Therefore, it is more likely that by administration of anti–IL-5 or CCR3 Abs (72, 73). The eosinophils contribute to T cell–independent IgA class switch- tissue immune microenvironment is suggested to influence the ing, which mainly occurs in the small intestinal lamina propria, downstream immune consequences mediated by eosinophils, where abundant numbers of eosinophils reside. However, leading either to exacerbation of local inflammatory responses eosinophils produce TGF-b, a cytokine critical for the Ab class or maintenance of tissue homeostasis (74). switching toward IgA in response to T cell–dependent Ags (2, 83). Therefore, in terms of TGF-b secretion, eosinophils can Eosinophils as modulators of intestinal immune responses: interaction be posited to play a supportive role in the induction of IgA with T cells class switching in organized lymphoid tissue. Notably, we observed an IgA deficiency in the intestinal lavage fluid and Accumulating evidence suggests a role for eosinophils as mod- serum of genetically modified eosinophil-deficient mice ulators of T cell–mediated immune responses. Several studies (Y. J. Jung and M. E. Rothenberg, unpublished observations), found that eosinophils can express MHC class II and co- which implicates gastrointestinal eosinophils as a regulator stimulatory molecules, which suggests a capacity to function of IgA class switching in the intestine. as APCs. Despite the fact that blood eosinophils do not ex- Downloaded from press MHC class II in the steady-state, human blood eo- Eosinophils as modulators of intestinal immune responses: role in sinophils stimulated with IL-3, IL-4, GM-CSF, and IFN-g metabolism express MHC class II molecules (75, 76). Although the Ag- presenting capabilities of small intestinal eosinophils have not The incidence of has increased rapidly worldwide, been examined in depth, intestinal eosinophils isolated from and obesity-associated diseases, including insulin resistance, mice were found to express only relatively low levels of CD86 type 2 diabetes, fatty liver disease, atherosclerosis, and stroke, http://www.jimmunol.org/ and MHC class II, which implies an inability to present Ags constitute major health problems (84). Inflammation is a key + feature of obesity, and infiltration of proinflammatory mac- to naive CD4 T cells under homeostatic conditions (77). + + Notably, eosinophils secrete an array of cytokines, such as IL- rophages, neutrophils, CD8 T cells, CD4 T cells, and mast 2, IL-4, IL-6, IL-10, and IL-12, along with TNF-a, which are cells is observed in visceral adipose tissue with obesity capable of activating dendritic cells (2). Moreover, it was re- (85). Meanwhile, in nonobese, normal visceral tissue of mice, ported that EDN can activate dendritic cells by stimulating eosinophils and alternatively activated macrophages are ob- the TLR2-signaling pathway of those cells and by inducing served, suggesting a role for eosinophils in adipose tissue their Th2-polarization capacity in mice (78). On the basis of metabolism (86). Alternatively activated macrophages in ad- these observations, eosinophils may constitute a portion of ipose tissue improve insulin sensitivity (glucose homeostasis), by guest on September 29, 2021 nonconventional APCs that promote the activity of dendritic and eosinophils are necessary for that specific subset of mac- cells, at least in the murine gastrointestinal tract (Fig. 1B). rophages (86, 87). Furthermore, the absence of eosinophils leads directly to adiposity and systemic insulin resistance in mice (88), implying a protective role for eosinophils against Eosinophils as modulators of intestinal immune responses: role in the development of type 2 diabetes (Fig. 1B). Maintenance of mucosal IgA class switching eosinophils in visceral adipose tissue is dependent on IL-5 and The gastrointestinal tract, exposed to potentially harmful com- IL-13, and ILC2s expressing both of these cytokines promote mensals and airborne and ingested pathogens, protects itself the accumulation of eosinophils in visceral adipose tissue (88). via production of IgA, the most abundant Ab in the Therefore, interaction between ILC2s and eosinophils not only human body for neutralization of microbes in a noninflam- supports survival of intestinal eosinophils as previously noted, it matory manner (79). Murine eosinophils in the bone marrow also seems to be implicated in metabolic homeostasis. are known to support the survival of plasma cells by secreting a proliferation-inducing ligand (APRIL) (80). Together with Conclusions B cell–activating factor, APRIL is known to induce IgA class Eosinophils have been considered to be end-stage effector switching in a T cell–independent manner (81). Therefore, cells that are involved in host protection against parasitic in- small intestinal eosinophils may have a role in the gastroin- fection and the development of inflammatory disorders. testinal tract’s T cell–independent IgA production, specifi- However, accumulating evidence now indicates that eosino- cally by producing APRIL. Although the involvement of phils are multifunctional leukocytes that have a broader role in intestinal eosinophils in IgA class switching has not been host responses against a wide range of infections (bacteria and examined directly, the impaired IgA production reported in viruses) and are potentially key modulators of the intestinal CD47-deficient mice suggests a potential role in IgA synthesis immune system. Likely, they may intimately interact and/or (82). As noted above, small intestinal eosinophils highly ex- regulate commensal intestinal microflora, especially in view press SIRP-a, a cognate receptor for CD47, and SIRP- of the antibacterial effect of their granule proteins (7) and a/CD47 signaling contributes to the prolonged survival of ability to modify innate immunity. The recent recognition of murine intestinal eosinophils by regulation of their degran- EGIDs, which are increasing rapidly in prevalence, calls at- ulation (16). The impaired production of IgA in CD47- tention to the potential importance of translating the molecular deficient mice may correlate with reduced viability of small and cellular immunological knowledge focused on gastroin- intestinal eosinophils. The constitutive presence of eosino- testinal eosinophils into clinical treatment strategies. Indeed, phils in the intestinal tissues suggests their potential role in the development of anti–eotaxin 1 (), anti–IL-5 1004 BRIEF REVIEWS: GASTROINTESTINAL EOSINOPHILS

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