Eosinophils in mucosal immune responses

Abstract

Eosinophils, multifunctional cells that contribute to both innate and adaptive immunity, are involved in the initiation, propagation, and resolution of immune responses, including tissue repair. They achieve this multifunctionality by expression of a diverse set of activation receptors, including those that directly recognize pathogens and opsonized targets, and by their ability to store and release preformed cytotoxic mediators that participate in host defense, to produce a variety of de novo pleotropic mediators and cytokines, and to interact directly and indirectly with diverse cell types, including adaptive and innate immunocytes and structural cells. Herein, we review the basic biology of eosinophils and then focus on new emerging concepts about their role in mucosal immune homeostasis, particularly maintenance of intestinal IgA. We review emerging data about their development and regulation and describe new concepts concerning mucosal eosinophilic diseases. We describe recently developed therapeutic strategies to modify eosinophil levels and function and provide collective insight about the beneficial and detrimental functions of these enigmatic cells.

Conflict of interest statement

Conflict of Interest: M.E.R. is a consultant for Immune Pharmaceuticals, Celsus and Receptos and has an equity interest in each and royalties from reslizumab, a drug being developed by Teva Pharmaceuticals. M.E.R. is an inventor of several patents owned by Cincinnati Children’s, and a set of these patents, related to molecular diagnostics, has been licensed to Diagnovus, LLC. J.T. has no potential conflicts to disclose.

Figures

Figure 1. Eosinophil Characteristics and Effector Functions

Eosinophil activation is mediated by a wide variety of surface receptors that respond to diverse stimuli, including cytokines, chemokines, bioactive lipids, and pathogen-associated molecular patterns. Upon activation, eosinophils promote host protection via direct effects on pathogens, immune responses by modulation of lymphocyte and dendritic cell function and inflammation via tissue damage, remodeling and mast cell activation. CCR, CC-chemokine receptor; CysLTR, cysteinyl leukotriene receptor; EMR, epidermal growth factor-like module containing mucin-like hormone receptor; Fc, fragment crystallizable; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; Ig, immunoglobulin; IL, interleukin; ILT, immunogloublin-like transcript; PAFR, platelet-activating factor receptor; PGDR, prostaglandin D2 receptor; PIR, paired immunoglobulin-like receptor; R, receptor; SIGLEC, sialic acid–binding immunoglobulin-like lectin; TGF, transforming growth factor; TLR, Toll-like receptor; TSLP, thymic stromal lymphopoietin.

Figure 2. Homeostatic Trafficking to Intestine

IL-5, and to a lesser extent IL-3 and GM-CSF, promote eosinophil development in the bone marrow, trafficking into the bloodstream and survival in the tissue. IL-13 induces eotaxin-1 release from inflammatory monocytes, which causes eosinophil recruitment to the intestine via ligation of CCR3. Entry of eosinophils into the intestine is mediated by binding of α4β1 integrin to VCAM-1, α4β7 integrin to MAdCAM1 and CD18 family members to ICAM-1. It has been proposed that after food consumption, the neurohormone vasoactive intestinal peptide (VIP) is secreted and activates type 2 innate lymphoid cells (ILC2) within the intestine to secrete IL-5 and IL-13. BM, bone marrow; C/EBPα, CCAAT/enhancer-binding protein alpha; CCR3, CC-chemokine receptor 3; CD, cluster of differentiation; EoP, eosinophil progenitor; GATA-1, GATA-binding protein 1; GM-CSF; granulocyte-macrophage colony-stimulating factor; HSC, hematopoetic stem cell; ICAM-1, intercellular adhesion molecule 1; ICSBP, interferon consensus sequence–binding protein; IL, interleukin; MAdCAM-1, mucosal vascular addressin adhesion molecule 1; PU.1, PU box binding protein; VCAM-1, vascular cell adhesion molecule 1.

Figure 3. Pathogenesis of EoE

TSLP is released from the epithelium and activates basophils and food antigen–presenting dendritic cells to induce Th2 polarization of naïve CD4+ T cells. Th2 polarization is aided by miR-21, which represses Th1 polarization by degradation of IL-12. These Th2 cells, in addition to invariant natural killer T (iNKT) cells and IL-13–producing FoxP3+ T cells, then secrete IL-13, which increases CCL26 and periostin (POSTN) expression and decreases desmoglein 1 (DSG1) expression in the epithelium. Decreased DSG1 level impairs barrier function, which forms a propagation loop by allowing further penetration of food antigen, and also leads to increased POSTN levels. The increased CCL26 and POSTN promote eosinophil recruitment from the bloodstream. The accumulating activated eosinophils further increase POSTN expression via the release of TGF-β and also cause epithelial cell cytotoxicity. CCL, CC-chemokine ligand; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; IL, interleukin; MBP, major basic protein; miR, microRNA; TGF, transforming growth factor; Th0, naïve T helper cell; Th1, type 1 T helper cell; Th2, type 2 T helper cell; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin.

Figure 4. Genetics of EoE

A. Candidate gene and genome-wide association studies have identified genetic variants in the 5q22 locus (TSLP/WDR36) and the 2p23 locus (CAPN14) as being associated with EoE susceptibility. B. Other genetic risk factors include variants associated in the CCL26, TGFB1, FLG, and CRLF2 genes. Additionally, the PTEN hamartoma tumor syndrome (PHTS) and several inherited connective tissue disorders (CTD) associated with TGF-β1 signaling are associated with EoE. C. The EoE-associated genes do not completely overlap with genes associated with other allergic disorders, as some are specific for EoE (e.g. CAPN14). This figure was derived in part from a publication with permission of the copyright holder. CAPN, calpain; CCL, CC-chemokine ligand; COL5A, collagen, type 5, alpha; CRLF, cytokine receptor–like factor; FBN1, fibrillin 1, FLG, filaggrin; HLA, human leukocyte antigen; HSF2BP, heat shock transcription factor binding protein 2; LRRC32, leucine-rich repeat–containing 32; MIR4675, microRNA 4675; ORMDL1/2, ORMDL sphingolipid biosynthesis regulator 1/2; TGF, transforming growth factor; TSLP, thymic stromal lymphopoietin; WDR, WD repeat–containing protein; XKR6, XK Kell blood group complex subunit–related family member 6.

Figure 5. Targets of Eosinophil-directed Biological Therapies

Eosinophil-directed biologic therapies function by either preventing eosinophil chemotaxis into tissues or impairing their survival upon recruitment. Eosinophil recruitment is hindered with neutralization of eotaxin by bertilimumab or blockade of CRTH2, whereas eosinophil survival is impaired with IL-5 neutralization by mepolizumab or reslizumab or IL-5Rα blockade with benralizumab. Additionally, selective eosinophil ablation occurs with cross-linking of EMR1 or SIGLEC-8. Finally, neutralization of TSLP by AMG 157 impairs both eosinophil recruitment and survival, as TSLP both directly activates eosinophils and promotes Th2 differentiation and cytokine production by activating basophils and dendritic cells. CCR, CC-chemokine receptor; CRTH2, chemoattractant-homologous receptor expressed on Th2 cells; EMR, epidermal growth factor-like module containing mucin-like hormone receptor; IL, interleukin; PGD2, prostaglandin D2; SIGLEC, sialic acid-binding immunoglobulin-like lectin; Th0, naïve T helper cell; Th2, type 2 T helper cell; TSLP, thymic stromal lymphopoietin; TSLPR, thymic stromal lymphopoietin receptor;.