Colgan, S. | Search bioRxiv

bioRxiv2025

Eosinophil-derived COX-2 protects against experimental colitis through the PGE2-IL-22 axis

Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (Cox)-2 (gene name, Ptgs2). Eosinophil-specific deletion of Cox-2 (Ptgs2fl/fleoCre+/-) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE2) signaling. Consistently, Ptgs2fl/fleoCre+/-mice exhibited reduced colonic PGE2 levels, while PGE2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE2 as a critical regulator of IL-22 production during colitis, uncovering a previously unrecognized eosinophil-ILC3 crosstalk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD. Significance StatementThe role of eosinophils in inflammatory bowel disease (IBD) has remained unresolved. We identify eosinophil-derived COX-2 as the main source of prostaglandin E2 (PGE2) in colitis, which drives IL-22 production by ILC3s to maintain epithelial protection. This discovery defines a protective eosinophil/PGE2/IL-22 circuit and reveals a therapeutic target to strengthen barrier defense in IBD.

immunology↗

bioRxiv2023

Microbiota-dependent indole production is required for the development of collagen-induced arthritis

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1{beta}; splenic ROR{gamma}t+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA.

immunology↗