Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production.

摘要: We hypothesized that the antimicrobial peptide cathelicidin has a physiological role in regulating gut inflammatory homeostasis. determined synergizes with LPS to facilitate its internalization and signaling via endosomic TLR4 colonic epithelium, evoking synthesis of human neutrophil chemoattractant, CXCL8 (or murine homolog, CXCL1). Interaction control CXCL8/CXCL1 was assessed colon epithelial cells, colonoids cathelicidin-null mice (Camp-/- ). Mechanistically, (LL-37), as an extracellular complex LPS, interacted lipid raft-associated GM1 gangliosides internalize activate intracellular TLR4. Two pathways converged on production: (1) p38MAPK-dependent pathway regulated by Src-EGFR kinases; and, (2) p38MAPK-independent, NF-κB-dependent pathway, MEK1/2-MAPK. Increased cathelicidin-dependent secretion mucosa activated blood-derived neutrophils. These effects occurred vitro at concentrations well below those needed for microbicidal function. The important immunomodulatory cathelicidins evident cathelicidin-null/Camp-/- mice, which had diminished CXCL1 secretion, decreased recruitment-activation reduced bacterial clearance when challenged colitis-inducing pathogen, Citrobacter rodentium. conclude addition known action, unique pathogen-sensing role, facilitating LPS-mediated intestinal responses, including production would contribute integrated tissue response recruit neutrophils during colitis.