Although the precise causes of inflammatory bowel disease (IBD) (e.g. ulcerative colitis and Crohn's disease) remain unclear, experimental and clinical studies indicate that an aberrant intestinal T-cell and macrophage (MΦ) response directed against luminal antigens, including commensal bacteria, is pathognomonic of these diseases [1–3]. Evidence indicates that the commensal intestinal microbiota are important to the exacerbation of the IBD phenotype: surgical diversion of the fecal stream effectively resolves Crohn's disease inflammation distal to the surgical site , and treatment with antibiotics decreases the risk of postoperative recurrence of Crohn's disease . A common feature of the cellular infiltrate in IBD, particularly ulcerative colitis, is eosinophils [6,7]. Although this cell population usually represents only a small percentage of the infiltrating leukocytes, eosinophil level has been shown to correlate with morphological changes to the gastrointestinal tract, disease severity, and gastrointestinal dysfunction [8–11]. Collectively, this clinical and experimental evidence suggests that eosinophils may play a role in combating commensal intestinal microbiota and infection in intestinal diseases such as IBD.
Consistent with this possibility, eosinophils possess the biological arsenal to fight bacterial infection. Eosinophils express various pattern recognition receptors [e.g. Toll-like receptors (TLRs), damage-associated molecular patterns (DAMPs)] enabling them to sense bacterial antigens, produce proinflammatory cytokines and cationic proteins [e.g. eosinophil cationic protein (ECP), major basic protein (MBP) and eosinophil peroxidase (EPO)] that possess antibacterial properties and release mitochondrial DNA-containing ‘traps’ into the extracellular space to kill bacteria. Indeed, recent in-vivo evidence indicates that mice with elevated eosinophil levels have reduced bacterial burden following infection, whereas mice depleted of eosinophils have increased bacterial burden. This inverse association of eosinophil level and postinfection bacterial burden suggests either a direct or indirect role for eosinophils in antibacterial immune response. However, there is clinical and experimental evidence to suggest that this cell population is not a major contributor to antibacterial immunity: systemic bacterial infection is associated with a rapid decline in eosinophil numbers, mice deficient in eosinophils or eosinophil-regulatory molecules [interleukin (IL)-5, CCR3 and eotaxin-1] appear to manage commensal microbe colonization and exposure to steady-state pathogens, and eosinophils reside in the gastrointestinal tract of germ-free mice. In this review, we discuss eosinophil bactericidal function and its possible role in eosinophil-related gastrointestinal diseases such as IBD.
EOSINOPHIL-RELATED GASTROINTESTINAL DISEASES
Eosinophil accumulation in the gastrointestinal tract is a common feature of numerous immunoglobulin (Ig)E-mediated and non-IgE-mediated gastrointestinal disorders including eosinophilic gastroenteritis , eosinophilic esophagitis (EoE) [13,14], IBD , and gastroesophageal reflux disease [15,16]. However, the function of eosinophils in gastrointestinal inflammation is not yet fully delineated. Eosinophils can augment gastrointestinal antigen-specific immune responses by acting as antigen-presenting cells and can potentiate gastrointestinal inflammation through the release of cytokines, chemokines, and lipid mediators, which can modulate gastrointestinal adhesion systems, leukocyte trafficking, tissue remodeling, and cellular activation states. Finally, eosinophils can serve as major effector cells, inducing tissue damage and dysfunction by releasing toxic granule proteins [17,18]. There is an abundance of clinical and experimental evidence to support a pathogenic role for eosinophils in eosinophilic gastrointestinal disorders such as EoE. However, there is also some evidence, at least in IBD, that eosinophils may have a dual function as both an end-stage effector cell and immunoregulatory cell [19–23].
INFLAMMATORY BOWEL DISEASES
The initial descriptions of eosinophil involvement in IBD occurred in the 1950s [24–27]; however, it was not until the 1960s and 1970s that more detailed analyses of eosinophil involvement in IBD disease activity and severity were performed. Bercovitz and Sommers  reported a six-fold increase in eosinophil levels in biopsy specimens from clinically active ulcerative colitis patients and observed that the increased eosinophil numbers in active ulcerative colitis correlated with necrosis, suggesting a pathogenic role for eosinophils in IBD. This potential role was supported by electron microscopy analyses that revealed ultrastructural evidence of eosinophil activation in patients with established Crohn's disease [29–31] and by immunohistochemical studies that demonstrated extracellular deposits of eosinophil granule proteins in biopsies of patients with Crohn's disease or ulcerative colitis [8,32,23]. Measuring the levels of eosinophil granule proteins in fecal matter and in intraluminal segmental perfusion fluid revealed an association between the amounts of extracellular granule proteins and disease relapse in patients with Crohn's disease [9,11,33,34]. Extracellular deposits of ECP are present in crypt abscesses and in areas with damaged surface epithelium but are decreased in inactive ulcerative colitis [9,23,35]. Elevated levels of eosinophils have been observed in colonic biopsy samples from adult patients with ulcerative colitis and Crohn's disease [9,36,37], and increased numbers of this cell and the eosinophil-derived granular proteins MBP, ECP, EPO, and eosinophil-derived neurotoxin (EDN) have been shown to correlate with morphological changes to the gastrointestinal tract, disease severity, and gastrointestinal dysfunction in ulcerative colitis [8–11,36,38].
Although the majority of the early patient-based studies demonstrated that eosinophil infiltration and activation were localized to the diseased areas of the gastrointestinal tract, suggesting a potential role for eosinophils in the initiation of mucosal injury, there is also evidence that eosinophils may play an immunomodulatory role . Sarin et al. demonstrated that there were increased eosinophil counts in active ulcerative colitis compared with inactive disease or nonulcerative colitis conditions but that there was no correlation between tissue eosinophil counts and clinical severity of ulcerative colitis. Furthermore, Lampinen et al. have reported that the level of activated eosinophils is higher in quiescent ulcerative colitis compared with active ulcerative colitis. The colonic mucosa of patients with quiescent ulcerative colitis is free of crypt distortion or active inflammation [40,41], and the decreased eosinophil degranulation in the presence of heightened eosinophil numbers suggests that eosinophils may play a role in the remodeling/repair of injured epithelium . Consistent with this possibility, in other eosinophil-associated diseases including allergic asthma and EoE, eosinophils are thought to contribute to tissue remodeling and repair [42–45]. Tissue remodeling and fibrotic response is mediated primarily via transforming growth factor (TGF)-β through its integral role in the regulation of the extracellular matrix and epithelial-mesenchymal cell transition and function . Increased levels of TGF-β-positive eosinophils have been identified in allergic asthma and EoE, and the loss of these cells was associated with reversal of tissue fibrosis and remodeling [47,48▪]. Intestinal fibrosis is also a complication of ulcerative colitis, but the mechanism of the fibrotic response is not yet delineated [49,50]. In a previous study, Lampinen et al. found increased levels of CD44high colonic eosinophils in quiescent ulcerative colitis. CD44 can be used as a marker of eosinophil activation [51,52], but it may also be associated with tissue remodeling in the resolution phase of inflammation. CD44 is the receptor for hyaluronic acid, and ligation of hyaluronic acid to CD44 has been demonstrated to induce eosinophil TGF-β production . It is interesting to speculate that eosinophils may contribute to the remodeling/fibrotic response in quiescent ulcerative colitis. Consistent with this possibility, eosinophils have been linked to fibroblast activation, fibrosis, and stricture formation in Crohn's disease [54,55].
Eosinophils develop in the bone marrow under direction of three main classes of transcription factors: zinc finger (GATA-1), ETS family member (PU.1), and CCAAT/enhancer-binding protein family (C/EBP) members [56–58]. GATA-1 is the most important transcription factor for eosinophil lineage specification as mice with a targeted deletion of the high-affinity GATA-binding site in the GATA-1 promoter lack eosinophils . Three cytokines that are particularly important in regulating eosinophil development, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), bind to receptors that share a common β chain but have unique α chains [17,60]. Notably, IL-5 is the most specific cytokine for eosinophil lineage commitment and is responsible for selective differentiation of eosinophils . Furthermore, IL-5 stimulates release of eosinophils from the bone marrow into the peripheral blood . Eosinophils can be activated through the engagement of receptors for cytokines, Igs, and complement. In response to these stimuli, eosinophils can secrete an array of proinflammatory cytokines (IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-16, IL-18, TGF-α, and TGF-β), chemokines (RANTES and eotaxin-1), and lipid mediators (platelet-activating factor and leukotriene C4) . These molecules have profound inflammatory effects, including upregulation of adhesion systems, modulation of cellular trafficking and cellular activation states, and activation/regulation of vascular permeability, mucus secretion, and smooth muscle constriction [17,18]. Eosinophils can also play a role in remodeling through expression of TGF-β1, which drives fibroblast proliferation and extracellular matrix deposition . Eosinophils can also activate the adaptive immune response by acting as antigen-presenting cells. They express major histocompatibility complex class II and costimulatory molecules (CD40, CD28, CD86, B7.1, and B7.2) [64–67] and secrete mediators that can promote lymphocyte proliferation, activation, and polarization [64,68–70]. Furthermore, eosinophils can release toxic granule proteins (MBP, ECP, EPO, EDN), which have been shown to cause damage to several tissues including the heart, brain, and bronchial epithelium [71–73].
EOSINOPHILS AND INNATE IMMUNITY
Eosinophils are a component of the innate immune system that, at baseline, resides within mucosal tissues, especially the gastrointestinal tract. Eosinophils are exquisitely sensitive to their environment due to expression of a plethora of receptors important in innate immune responses. For example, eosinophils are equipped to respond to pathogen-associated molecular patterns as well as DAMPs, suggesting a contributing role in response to pathogens and damaged tissues that may result from focal infections. Upon activation, eosinophils release preformed and de-novo-synthesized mediators, including granule proteins, cytokines, chemokines, enzymes, and growth factors, which mediate the diverse biologic activity of eosinophils in infection and inflammation.
PATTERN RECOGNITION RECEPTORS
Eosinophils have also been shown to express a number of TLRs including TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, and TLR-10 [74–76]. The level of TLR expression on the eosinophils is low relative to other granulocytes (e.g. neutrophils) except for relatively elevated levels of TLR-7/TLR-8 . Functional analysis using TLR-specific ligands revealed that TLR-7/TLR-8 ligands (R-848) induced eosinophil activation (superoxide production) and prolonged eosinophil survival . Cytokines, including interferon (IFN)-γ, have been shown to regulate the expression of TLR-7/TLR-8 .
EOSINOPHIL GRANULE PROTEINS
Eosinophil granules contain a crystalloid core composed of MBP-1 and MBP-2, and a matrix composed of ECP, EDN, and EPO . MBP, ECP, and EDN are ribonucleases and have been shown to possess antiviral activity, and ECP causes voltage-insensitive, ion-selective toxic pores in the membranes of target cells, possibly facilitating the entry of other cytotoxic molecules [79–82]. ECP also has a number of additional, noncytotoxic activities including suppression of T-cell proliferative responses and of Ig synthesis by B cells, mast cell degranulation, and stimulation of airway mucus secretion and of glycosaminoglycan production by human fibroblasts . MBP has been shown to directly alter smooth muscle contraction responses by dysregulating vagal muscarinic M2 and M3 receptor function and to promote mast cell and basophil degranulation [84–86]. MBP has also been recently implicated in regulating peripheral nerve plasticity . EPO catalyzes the oxidation of pseudohalides [thiocyanate (SCN−)], halides [chloride (Cl−), bromide (Br−), iodide (I−)], and nitric oxide metabolities (nitrate and nitrite) to form highly reactive oxygen species (hypohalous acids) and reactive nitrogen metabolites (perioxynitrate), respectively. These molecules oxidize nucleophilic targets on proteins, promoting oxidative stress and subsequent cell death by apoptosis and necrosis [88–90].
EOSINOPHILS AND DNA TRAPS
Neutrophils and macrophages are considered the primary cells involved in combating infection. Neutrophils employ the three primary strategies of phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to defend against bacteria. Neutrophils can phagocytose the bacteria and subsequently eliminate the microbe in specialized phagolysosome compartments. Neutrophils can also degranulate, whereby the neutrophil releases antimicrobial molecules including defensins, cathelicidins, myeloperoxidase, BPI, and serine proteases (e.g. elastase and cathepsin G) to kill bacteria. Additionally, neutrophils can form NETs, which arise from the release of the neutrophil's nuclear contents (as decondensed chromatin) into the extracellular space to interact with the array of antimicrobial peptides released through neutrophil degranulation [91,92]. Recent studies indicate that eosinophils also have the capacity to release mitochondrial DNA-containing ‘traps’ into the extracellular space [93▪▪]. Generation of eosinophil-derived extracellular traps can be stimulated by thymic stromal lymphopioetin (TSLP), IL-5, or IFN-γ and by a mechanism dependent upon reactive oxygen species [93▪▪,94▪].
EOSINOPHILS AND INFECTION
Eosinophils predominantly reside at mucosal surfaces colonized by microorganisms, such as the gastrointestinal and respiratory tract and uterus. Under homeostatic noninflammatory conditions, eosinophils are predominantly localized to gastrointestinal tract and uterus . There is evidence to support increased numbers of eosinophils during bacterial infection. For example, eosinophil levels in the peripheral blood and rectum of patients afflicted with the diarrhea-inducing pathogen Shigella are increased . However, a prominent role for eosinophils in clearing infections remains uncertain as a marked decrease in circulating eosinophils, or eosinopenia, has long been associated with acute bacterial infections in patients . Indeed, eosinopenia has been shown to be a sensitive and reliable marker for distinguishing between noninfectious and infection-associated sepsis in the ICU setting [97,98]. Increased margination and recruitment of eosinophils to sites of infection may contribute to the acute decline in circulating eosinophils associated with bacterial infections, but the mechanism for prolonged depletion remains undefined. Although peripheral blood eosinophil numbers may rapidly diminish with acute infection, this marked reduction can be accompanied by increased serum levels of the eosinophil granule protein ECP, which suggests eosinophil activation and degranulation . Consistent with this possibility, in-vitro studies indicate that eosinophils can phagocytose and kill bacteria including Staphylococcus aureus and Escherichia coli, although not as efficiently as neutrophils . Assessment of the diversity of antibacterial activity of human eosinophils revealed that this cell is responsive to gram-positive and gram-negative bacteria . Gram-positive (Streptococcus peroris and Clostridium perfringens) and gram-negative (Campylobacter jejuni and E. coli) organisms induced eosinophil chemotaxis, respiratory burst, and degranulation and release of ECP and MBP . Furthermore, incubation of purified murine eosinophils isolated from IL-5 transgenic mice multiplicity of infection of 10 killed 40% of viable Pseudomonas aeruginosa[102▪▪]. Notably, isolated eosinophil cationic granule proteins led to reduced bacteria colony counts, indicating that the antibacterial properties of eosinophils were mediated in part through the release of cationic proteins [102▪▪]. These data are consistent with previous in-vitro studies demonstrating potent antibacterial properties of MBP, ECP, and EPO. Human MBP and ECP killed S. aureus (502A) and E. coli (ML-35) in a time-dependent, concentration-dependent, temperature-dependent, and pH-dependent manner . Similarly, incubation of partially purified guinea pig EPO killed E. coli (11775) . The molecular basis of eosinophil granule protein antibacterial activity is not fully delineated. However, both MBP-mediated and ECP-mediated bacterial killing appears to involve bacterial ingestion and permeabilization of the outer membrane [103,105] combined. ECP binds to lipopolysaccharides and peptidoglycans with high affinity via its N-terminal region, and it is thought that ECP activates cytoplasmic membrane depolarization of S. aureus and agglutination and death of E. coli through this interaction . However, recent evidence indicates that there are regions within ECP that also possess bactericidal activity independent of membrane association and destabilization . EPO activity is primarily via an EPO-hydrogen peroxide-halide bactericidal system . However, EPO causes oxidative damage in presence of nitrite (NO2−) by inducing protein nitration of tyrosyl residues . Although cytotoxic granule proteins are thought to be major contributors to the bactericidal potential of eosinophils, there is evidence that superoxide production via eosinophil-derived NADPH oxidase can also kill bacteria . However, this evidence also suggests that the majority of the NADPH oxidase-dependent activity is in conjunction with the EPO-hydrogen peroxide-halide bactericidal system [107,108].
Although multiple in-vitro studies have demonstrated antibacterial properties for eosinophils, infection-associated eosinopenia has been well documented (e.g. in experimental models of E. coli pyelonephritis and S. pneumoniae abscesses) . Peripheral eosinophil counts have also been noted to decrease in newborn infants who acquire bacterial infections . In addition, studies of adults who are admitted to the hospital with blood cultures positive for bacterial growth have shown that the percentage of eosinophils in the peripheral blood smear decreased as the number of bacteria-positive blood cultures per patient increased . Further, eosinopenia has been shown to be a sensitive and reliable marker for distinguishing between noninfectious and infection-associated sepsis in the ICU setting [97,98]. Interestingly, intravenous administration of lipopolysaccharide (endotoxin) to normal humans resulted in a long-lasting depression in blood eosinophil counts, suggesting that exposure to microbial products is sufficient to induce eosinopenia .
There have also been recent experimental studies assessing the antibacterial properties of eosinophils in vivo in mice [102▪▪]. Intraperitoneal challenge of IL-5 transgenic mice, which have a profound peripheral blood and tissue eosinophilia, with P. aeruginosa leads to increased bacterial clearance compared with wild-type mice. Conversely, mice deficient in eosinophils had impaired clearance of P. aeruginosa. Notably, adoptive transfer of eosinophils improved bacterial clearance, clearly establishing an eosinophil-specific role in P. aeruginosa clearance [102▪▪]. In conjunction with these findings, the demonstration that administration of eosinophil granule proteins was sufficient to improve bacterial clearance in vivo suggests that eosinophil-dependent bactericidal effects are mediated via granule proteins [102▪▪].
It is important to appreciate that although eosinophils possess bactericidal properties, there is also evidence that suggests that IL-5 can modulate infection independent of eosinophils. Recently, investigators have demonstrated a role for IL-5 in sepsis. Moreover, employing the polymicrobial sepsis model, investigators demonstrated a link between IL-5 deficiency and increased bacterial burden and mortality during sepsis [112▪▪]. Conversely, therapeutic administration of IL-5 improved mortality [112▪▪]. Notably, IL-5 transgenic mice backcrossed onto an eosinophil-deficient background had similar mortality rates as eosinophil-competent IL-5 transgenic mice, revealing that IL-5-mediated effects are independent of eosinophils; the IL-5-mediated effects appeared to be related to neutrophil and monocyte function. Interestingly, human neutrophils and monocytes were shown to express IL-5Rα, and IL-5 induced cytokine production and macrophage phagocytosis and survival [112▪▪]. In-vitro and in-vivo data revealed that IL-5 bactericidal activity was dependent on macrophages [112▪▪]. Collectively, these studies indicate that IL-5 and eosinophils possess antibacterial activity, however, some of the IL-5-mediated effects can occur independently of eosinophil function.
The contribution of eosinophils to bacterial infection remains elusive. Eosinophils express the necessary innate immune sensors to detect bacteria and express cytolytic granule proteins with effective bactericidal activity. However, the experimental and clinical evidence supporting their role as major contributors of intestinal and systemic antibacterial function is limited. Thus, eosinophils may have alternative roles in intestinal inflammatory diseases that are driven by bacterial antigens. Eosinophils may be involved in tissue repair and remodeling. Several experimental studies indicate an important role for eosinophil-derived cytokines (e.g. IL-13) in fibrotic responses [44,113,114]. Alternatively, eosinophils may orchestrate the antibacterial inflammatory cascade, recruiting and activating other granulocytes and myeloid cells through cytokines, chemokines, and lipid mediators to provide an effective bacterial immunity. A number of gastrointestinal diseases are associated with intestinal epithelial injury; for these diseases, eosinophils could permit re-epithelization of the intestinal wall via released granule proteins, which can facilitate clearance of apoptic host and foreign cells.
Clinical and experimental studies indicate that eosinophils do contribute to the pathogenesis of IBD; however, it remains unclear whether the host eosinophilic response is directed against infection or is directed to promote tissue repair. Further experimental investigation is required to illuminate the roles of eosinophils in infection and intestinal immunity.
I would like to thank Shawna Hottinger for editorial assistance. Grant Support: This work was supported by NIH R01 AI073553 and DK090119.
Conflicts of interest
Disclosures: S.P.H. is a consultant for Immune Pharmaceuticals. Other authors have none to declare.
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