Author

Vu NgoFollow

Author ORCID Identifier

https://orcid.org/0000-0002-9820-0443

Date of Award

5-4-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Timothy L. Denning

Second Advisor

Andrew Gewirtz

Third Advisor

Didier Merlin

Abstract

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.

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