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 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.