Dsilva, A. | bioRxiv Science

bioRxiv2026

Differential roles for IL-4Rα and IL-13Rα1in immune cell infiltration and epithelial remodeling in experimental eosinophilic gastritis

RationaleEosinophilic gastritis (EoG) is a chronic inflammatory disease characterized by infiltration of eosinophils and mast cells, epithelial remodeling, and fibrosis. Although EoG is increasingly recognized as a distinct type 2 inflammatory disease, the cellular and molecular events that drive disease pathogenesis remain poorly understood. This is due in part to the absence of robust and physiologically relevant experimental models that recapitulate human disease. MethodsExperimental EoG was induced in wild type and Il13ra1-/-mice by repeated intragastric oxazolone challenges in skin-sensitized mice. IL-4R1 was neutralized using antibodies. Gastric histopathology was determined by H&E, anti-Ki67, chloroacetate esterase and anti-MBP staining. Gastric RNA was subjected to RNA sequencing. ResultsExperimental EoG resulted in robust gastric eosinophilia, mastocytosis, epithelial remodeling, and subepithelial fibrosis. Transcriptomic profiling of gastric tissue revealed broad upregulation of type 2 cytokine and epithelial-remodeling genes, including Il4ra, Il4i1, Ccl5, Muc4, Mmp10, Mcpt1/2, Areg, Pparg and Tff2. The transcriptome profile of experimental EoG was markedly distinct from that of experimental EoE despite both models being initiated by oxazolone, suggesting that identical inflammatory triggers elicit tissue-specific and context-dependent transcriptional programs. Blockade of IL-4R signaling abrogated both eosinophil and mast cell infiltration and attenuated epithelial remodeling, whereas genetic deletion of Il13ra1 selectively suppressed epithelial remodeling without affecting inflammatory cell recruitment. ConclusionThese findings establish experimental EoG as a robust model for dissecting the cellular and molecular mechanisms driving gastric type 2 inflammation. They further define receptor-specific roles for IL-4R and IL-13R1 in coordinating immune infiltration and epithelial remodeling in EoG.

immunology↗

bioRxiv2025

Distinct roles for thymic stromal lymphopoietin (TSLP) and IL-33 in experimental eosinophilic esophagitis

RationaleThymic stromal lymphopoietin (TSLP) and IL-33 are alarmins implicated in EoE pathogenesis by activating multiple cells including mast cells (MCs). Whether TSLP or IL-33 have a role in EoE and whether their activities are distinct requires further investigation. MethodsExperimental EoE was induced in wild type (WT) Il33-/-and Crlf2-/- mice. TSLP or IL-5 were neutralized using antibodies. Esophageal histopathology was determined by H&E, anti-Ki67, anti-CD31 and anti-MBP staining. Esophageal RNA was subjected to RNA sequencing. Bone marrow-derived MCs were activated with TSLP and IL-13 was determined (ELISA) ResultsTSLP and IL-33 were overexpressed in human and experimental EoE. Human and mouse esophageal MCs displayed the highest level of Crlf2 (TSLPR) compared to other immune cells. Crlf2-/- mice were nearly-completely protected from EoE, and TSLP neutralization resulted in decreased basal cell proliferation, eosinophilia, lamina propria thickening and vascularization. Induction of experimental EoE in Il33-/- mice resulted in reduced eosinophilia but no alterations in tissue remodeling were observed compared to WT mice. RNA sequencing revealed that TSLP regulates the expression of key genes associated with human EoE (e.g. eotaxins, Il19, Klk5, Flg, Il36rn, Il1r2) and suggest a role for TSLP in regulating IL-1 signaling, barrier integrity and epithelial cell differentiation. Experimental EoE was characterized by a MC-associated gene signature and elevated MCs. Activation of MCs with TSLP resulted in secretion of IL-13. ConclusionTSLP and IL-33 have non-redundant functions in experimental EoE. This study highlights TSLP as an upstream regulator of IL-13 and a potential therapeutic target for EoE.

immunology↗