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

Autor: Ravi Holani, Chathurika Rathnayaka, Graham A.D. Blyth, Anshu Babbar, Priyoshi Lahiri, Daniel Young, Antoine Dufour, Morley D. Hollenberg, Derek M. McKay, Eduardo R. Cobo
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Innate Immunity, Pp 1-18 (2022)
Druh dokumentu: article
ISSN: 1662-811X
1662-8128
00052612
DOI: 10.1159/000526121
Popis: 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.
Databáze: Directory of Open Access Journals
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