Interleukin 9 Alters Epithelial Barrier and E‐cadherin in Eosinophilic Esophagitis

Abstract

Background: Eosinophilic esophagitis (EoE) is a chronic Th2-assocated inflammatory condition accompanied by substantial impairments in epithelial barrier function and increased numbers of interleukin 9 (IL-9) expressing inflammatory cells. While IL-9 is known to affect barrier function in the intestine, the functional effects of IL-9 on the esophagus are unclear. Herein we aimed to understand the expression of the IL-9 receptor and effects of IL-9 on the epithelium in EoE. Methods: We used esophageal biopsies from pediatric EoE patients with active and inactive disease to analyze the expression of the IL-9 receptor, the adherens junction protein E-cadherin and the tight junction protein claudin-1. We treated primary human esophageal epithelial cells with IL-9 to understand its effects on E-cadherin expression and function. Results: Active EoE subjects had increased epithelial expression of IL-9 receptor mRNA and protein (P < 0.05) and decreased membrane bound E-cadherin (P < 0.01) and claudin-1 (P < 0.05) expression. IL-9 receptor expression and mislocalized claudin-1 positively correlated and while membrane bound E-cadherin expression negatively correlated with the degree of histologic epithelial remodeling (P < 0.05). IL-9 decreased epithelial resistance in stratified primary human esophageal epithelial cells (P < 0.01) and membrane bound E-cadherin in epithelial cell monolayers (P < 0.01). Conclusions: These data suggest that IL-9, its receptor, and its effects on E-cadherin may be important mechanisms for epithelial barrier disruption in EoE.

Junctional complexes in epithelial cells: sentinels for extracellular insults and intracellular homeostasis

“…Adherens junctions are more frequently observed in the upper layers in the epidermis (Fig. 1A) [22,23], whereas the adherens junction receptor epithelial-cadherin (E-cadherin) is primarily localized to the middle and basal layers of the oesophageal epithelium [36]. Desmosomes are found in all living layers of most stratified epithelium (Fig.…”

Local Antigen Deposition in Eosinophilic Esophagitis: Implications for Immune Activation

“…9 IL-5 promotes eosinophil accumulation, and eosinophil-derived cytokines like IL-9 promote mast cell accumulation and E-cadherin loss. 10,11 Adaptive Th2 and innate lymphoid cells release IL-4 and IL-13 to promote B-cell class switch to IgE. 12 Preloaded FcεRI receptors on mast cells 13 and basophils cause degranulation in response to local antigen and release preformed cytokines such as transforming growth factor- β 1 14 and tumor necrosis factor- α with ensuing fibrosis, smooth muscle hypertrophy, and contractile changes (Figure 1).…”

Development and Application of a Functional Human Esophageal Mucosa Explant Platform to Eosinophilic Esophagitis

“…Immunofluorescence staining for E-cadherin (Fig. 4b) further confirmed sustained squamous differentiation after 14 days with junctional protein reorganization induced by the cytokine cocktail 28 . TGFβ1 treatment of LSM bundles also significantly induced fibronectin and phospholamban expression from 1 to 3 weeks in culture (p < 0.001) (Fig.…”

“…The value of this approach is supported by the ability of our esophageal mucosa platform to mimic EoE at the levels of global transcriptional induction as assessed by the EDP transcription profile and alterations in esophageal stiffness. Treatment with an EoE-like Th2 cytokine cocktail induced disease-relevant gene transcription, alterations in E-cadherin organization of the epithelial barrier as occurs in vivo in the active EoE disease state 28 , and also increased mucosal stiffness leading to compliance properties similar to those obtained from EoE patients during endoFLIP 36 . Given this applicability of the platform to one esophageal disease, we suggest that our studies could help investigators to elucidate esophageal function in response to various stimuli including cytokines, acid, carcinogens, and therapeutic drugs.…”