Differential roles for IL-4Rα and IL-13Rα1in immune cell infiltration and epithelial remodeling in experimental eosinophilic gastritis
Rationale: Eosinophilic 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. Methods: Experimental EoG was induced in wild type and Il13ra1-/- mice by repeated intragastric oxazolone challenges in skin-sensitized mice. IL-4Ralpha1 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. Results: Experimental 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-4Ralpha; signaling abrogated both eosinophil and mast cell infiltration and attenuated epithelial remodeling, whereas genetic deletion of Il13ralpha1 selectively suppressed epithelial remodeling without affecting inflammatory cell recruitment. Conclusion: These 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-4Ralpha; and IL-13Ralpha1 in coordinating immune infiltration and epithelial remodeling in EoG. ### Competing Interest Statement Ariel Munitz is a consultant for Glaxo Smith Kline, Astra Zeneca, Sanofi, Oravax, Sartorious and is an inventor of patents owned by the Tel Aviv University. The remaining authors disclose no conflicts. Israel Science Foundation, 542/20 United States-Israel Binational Science Foundation, 2023029 Israel Cancer Research Fund Israel Cancer Association
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