Integrin αM activation and upregulation on esophageal eosinophils and periostin‐mediated eosinophil survival in eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is an increasingly recognized allergic disease associated with dysphagia and esophageal fibrosis. We aimed to determine expression patterns of specific eosinophil integrins that promote eosinophilic infiltration of the esophageal epithelium, and to determine how key EoE-related cytokines influence eosinophil activation and survival. Esophageal and peripheral eosinophils were isolated from 20 adult subjects with EoE for immunophenotyping and integrin profiling using multicolor flow cytometry and immunohistochemistry. Expression signatures of eosinophil integrins were further assessed by immunohistochemistry using serial sections of esophageal biopsy specimens. Purified eosinophils were used to assess the effect of EoE-relevant cytokines and recombinant periostin on expression of known eosinophil integrins and eosinophil survival and activation. We found that resting eosinophils express high levels of the β2-pairing integrins αL and αM, and lower levels of α4, α6 and α4β7. The migration of peripheral eosinophils to the esophagus is characterized by the specific induction of αM, and a significant increase in the proportion of αM in high-activity conformation. Periostin, a secreted extracellular matrix protein that is significantly overexpressed in EoE, enhances eosinophil survival, and this effect is mediated by αM interaction. Integrin αM is a specific marker of activated tissue eosinophils in EoE, and promotes eosinophil survival through interactions with periostin. The ability of αMβ2 to mediate eosinophil tissue residency via periostin represents a key mechanism for disease development and a potential therapeutic target in EoE.

Medical and dietary management of eosinophilic esophagitis

“…18 This observation is in congruence with the recent finding that the migration of peripheral eosinophils to the esophagus and their survival in situ are linked to the up-regulation and conformational change of αMβ2, also known as CD11b/CD18, integrin, and its interaction with periostin, which is also highly expressed in EoE. 19,20 Treatment with budesonide for 12 weeks, or as for as short a period as 15 days, has been shown to achieve histologic, endoscopic, and clinical improvement in adolescent to adult EoE patients. 21,22 Budesonide treatment in adult EoE patients reduces esophageal eosinophil density, absolute peripheral eosinophilia, and serum levels of CCL17, CCL18, CCL26, eosinophil-cationic protein, and mast cell tryptase.…”

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

“…Blood eosinophils are broadly identified by flow cytometry as SSC hi SiglecF/8 + CD62L + CCR3 + IL5Rα + leukocytes (reviewed in [4]), and express surface integrins including α L β 2 (CD11a/CD18), α M β 2 (CD11b/CD18d), α D β 2 (CD11d/CD18), α6 (CD49f), α 4 β 7 (CD49d/β 7 ), and β 1 (CD29) integrins (e.g., α 4 β 1 ) in low-activation conformations in the steady state [38,39]. Whether systemic signals within the context of eosinophilic inflammatory diseases may temporarily modulate surface receptors on circulating eosinophils, including integrin expression, activation markers and growth factor receptors, is an area of active current research, with most progress to date coming from studies in asthmatics.…”

“…Akin to eosinophils recruited to asthmatic airways, Vimilathas et al demonstrated increased expression of total high-activity conformation αM (CD11b) integrin on esophageal eosinophils from EoE patients, expression of which promoted eosinophil survival through interactions with periostin [38]. Ultrastructural studies demonstrate esophageal tissue eosinophils undergo distinct modes of secretion (i.e., piecemeal degranulation versus cytolysis), the latter presumably indicative of pro-inflammatory functions, in patients with EoE [66].…”

“…Periostin is linked to eosinophil recruitment to inflamed airways in asthmatics and idiopathic pulmonary fibrosis (IPF) patients; serum periostin predicts airway eosinophils in steroid-resistant asthma [96], and predicts disease progression in IPF [97]. Periostin is likewise highly upregulated in the esophagus of EoE patients [38,63], and in a mouse model of EoE, periostin deletion was associated with defective eosinophil esophageal recruitment [63]. Beyond regulating eosinophil recruitment, periostin supports α M β 2 (CD11b/CD18)-mediated adhesion and migration of IL-5, GM-CSF or IL-3 stimulated eosinophils, promotes eosinophil adhesion to fibronectin, prolongs eosinophil survival, and enhances eosinophil superoxide anion production and secretion of EDN [38,62,63,87,98].…”

Climbing New Mountains: How Antibodies Blocking α4β7 Integrins Tamed Eosinophilic Inflammation of the Intestinal Tract

“…Since eosinophils also bear α4β7 integrins and can bind to vascular endothelial MAdCAM-1, vedolizumab may be useful in EGIDs by directly inhibiting eosinophil intestinal homing [9]. Moreover, since Th2-derived cytokines Fig.…”