Cathelicidins Induce Toll-Interacting Protein Synthesis to Prevent Apoptosis in Colonic Epithelium

Cathelicidin peptides secreted by leukocytes and epithelial cells are microbicidal but also regulate pathogen sensing via toll-like receptors (TLRs) in the colon by mechanisms that are not fully understood. Herein, analyses with the attaching/effacing pathogen Citrobacter rodentium model of colitis...

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Main Authors: Ravi Holani (Author), Chathurika Rathnayaka (Author), Graham A.D. Blyth (Author), Anshu Babbar (Author), Priyoshi Lahiri (Author), Daniel Young (Author), Antoine Dufour (Author), Morley D. Hollenberg (Author), Derek M. McKay (Author), Eduardo R. Cobo (Author)
Format: Book
Published: Karger Publishers, 2022-09-01T00:00:00Z.
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Summary:Cathelicidin peptides secreted by leukocytes and epithelial cells are microbicidal but also regulate pathogen sensing via toll-like receptors (TLRs) in the colon by mechanisms that are not fully understood. Herein, analyses with the attaching/effacing pathogen Citrobacter rodentium model of colitis in cathelicidin-deficient (Camp−/−) mice, and colonic epithelia demonstrate that cathelicidins prevent apoptosis by sustaining post-transcriptional synthesis of a TLR adapter, toll-interacting protein (TOLLIP). Cathelicidins induced phosphorylation-activation of epidermal growth factor receptor (EGFR)-kinase, which phosphorylated-inactivated miRNA-activating enzyme Argonaute 2 (AGO2), thus reducing availability of the TOLLIP repressor miRNA-31. Cathelicidins promoted stability of TOLLIP protein via a proteosome-dependent pathway. This cathelicidin-induced TOLLIP upregulation prevented apoptosis in the colonic epithelium by reducing levels of caspase-3 and poly (ADP-ribose) polymerase (PARP)-1 in response to the proinflammatory cytokines, interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Further, Camp−/− colonic epithelial cells were more susceptible to apoptosis during C. rodentium infection than wild-type cells. This antiapoptotic effect of cathelicidins, maintaining epithelial TOLLIP protein in the gut, provides insight into cathelicidin's ability to regulate TLR signaling and prevent exacerbated inflammation.
Item Description:1662-811X
1662-8128
10.1159/000526121