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

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Inflammatory bowel disease (IBD) involves immune dysregulation and epithelial barrier defects.
• The role of eosinophils in IBD pathogenesis is poorly understood.
• Eosinophils infiltrate the gut mucosa in IBD, but their specific contribution to disease outcomes remains controversial.

Purpose of the Study:

• To investigate the role of eosinophils in IBD pathogenesis.
• To identify molecular mechanisms by which eosinophils influence intestinal inflammation.
• To explore potential therapeutic targets within eosinophil-mediated pathways in IBD.

Main Methods:

• RNA sequencing of colonic eosinophils from dextran sulfate sodium (DSS)-treated mice.
• Generation and analysis of eosinophil-specific cyclooxygenase-2 (COX-2) knockout mice (Ptgs2^fl/fleoCre^+/-).
• Induction of colitis using DSS and trinitrobenzene sulfonic acid (TNBS) models.
• Assessment of disease severity, colon histology, and cytokine production (IL-22).
• Investigation of prostaglandin E2 (PGE2) signaling pathways.

Main Results:

• Colonic eosinophils from DSS-treated mice showed upregulated COX-2 (gene name, Ptgs2).
• Eosinophil-specific deletion of COX-2 exacerbated DSS- and TNBS-induced colitis, with increased weight loss, disease activity, and epithelial injury.
• Deletion of COX-2 in eosinophils reduced IL-22 production by type 3 innate lymphoid cells (ILC3s).
• Administration of recombinant IL-22 or a PGE2 analog restored mucosal protection and ameliorated colitis phenotypes.
• Reduced colonic PGE2 levels were observed in mice lacking eosinophil COX-2.

Conclusions:

• Eosinophil-derived COX-2 and PGE2 are critical regulators of IL-22 production during colitis.
• A previously unrecognized crosstalk between eosinophils and ILC3s, mediated by COX-2/PGE2, safeguards the intestinal barrier.
• This eosinophil-ILC3 axis represents a promising therapeutic target for IBD.