Author ORCID Identifier
Date of Award
Doctor of Philosophy (PhD)
Timothy L. Denning
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Cytokines have a critical role in the pathogenesis of IBD, in which they control multiple aspects of the inflammatory response. One such cytokine, Interleukin (IL-36) is overexpressed in both experimental and human IBD and may play both pathogenic and protective roles, depending on the context. The IL-36 signaling pathway induces IL-22, a cytokine that is critical in repair and regeneration of the gut epithelium during inflammation. However, the mechanism by which IL-36 induces IL-22 and promotes barrier repair is incompletely understood.
We observed a cytokine network, in which, IL-36γ/IL-36R signaling is an important upstream driver of IL-22 and antimicrobial peptide (AMP) production to protect the host against acute intestinal damage. We have shown that IL-36γ is a potent inducer of IL-23. IL-36γ–induced IL-23 requires Notch2-dependent dendritic cells (DCs). The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits. Consistent with in vitro observations, IL-36R-/- mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R was rescued by treatment with exogenous IL-23. We also found that IL-36R-/- mice are defective of host protection during enteropathogenic bacterial infection. The IL-36 signaling cascade is essential in both early and late phases of immune defense against C. rodentium infection. During the early stage of infection, IL-36 induced the production of IL-22 by innate lymphoid cells 3 (ILC3s) via IL-23; and during the late phase, IL-36 stimulated the production of IL-22 from T-cells via IL-6. Intriguingly, in the experimental chronic colitis, IL-36R-/- mice display reduced disease severity and are associated with decreased production of inflammatory cytokines and enhance expression of Foxp3 regulatory T cells. Collectively, these findings highlight context-dependent, protective and pathogenic contribution of the IL-36R signaling pathway and the potential for optimally manipulating this pathway for better treatment of intestinal inflammation.
Ngo, Vu, "IL-36R Signaling and Gut Immunity." Dissertation, Georgia State University, 2020.
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