Cathelicidin senses enteric pathogen Salmonella typhimurium/LPS for colonic chemokine generation: a new innate immune role for a host defense peptide

The mechanisms by which epithelia identify and respond to pathogens are manifold, nuanced and complex. Here, using human-colon derived HT29 epithelial cells, mouse and human primary colonoids, and cathelicidin null (Cramp) mice, we report a novel immunoregulatory role for the antimicrobial peptide, cathelicidin, that was found to recognize and synergise with Salmonella typhimurium or its derived virulence factor lipopolysaccharide (LPS) to promote epithelial synthesis of the chemokine IL-8/KC for neutrophil recruitment/activation during infectious colitis. Mechanistically, cathelicidin facilitated the internalization of LPS via GM1 lipid rafts and subsequent TLR4 activation to promote IL-8 production. Furthermore, IL-8 output required the integrated activity of two signal transduction pathways: NF-κB and MEK 1/2 kinase signaling was required for IL-8 mRNA synthesis, while Src-EGFR-p38MAPK (NF-κB independent) activity underlay IL-8 mRNA stabilization. This immunomodulatory function of cathelicidin was key in colon defense, since Cramp-/- mice infected with a natural murine Gram negative intestinal pathogen, Citrobacter rodentium, displayed diminished KC secretion, impaired mobilization and reduced clearance of the bacteria. Occurring at concentrations lower than those necessary for anti-microbial activity, cathelicidin’s capacity to sense pathogens/LPS and enhance neutrophil recruitment reveals a novel function for this peptide in directing innate immunity which may be of pivotal importance in the control of infections colitis.