Defence molecules in intestinal innate immunity against bacterial infections

Abstract

Antimicrobial proteins are key effector molecules of innate immunity. The review discusses recent progress in understanding the function of these host defence molecules in intestinal physiology. All antimicrobial proteins can inhibit or kill bacteria in vitro, but differ markedly in their localization, regulation, and additional activities. alpha-Defensins are expressed constitutively in human neutrophils and small intestinal Paneth cells, where they require proteolytic processing and signal-induced release to be active in the intestinal lumen. Neutrophil-derived alpha-defensins can inhibit angiogenesis. Cryptdin-related sequence peptides form a subfamily of alpha-defensins in murine but not human Paneth cells that can form covalently linked heterodimers, leading to increased structural diversity and antimicrobial target range. Human beta-defensins (hBD) are expressed prominently in epithelial cells of the intestinal tract and other organs exposed to the environment. Their epithelial production is either constitutive, as exemplified by hBD-1, or strongly inducible, as shown for hBD-2,-3, and -4. Human cathelicidin, LL-37/hCAP18, is expressed constitutively by differentiated epithelial cells in the colon and stomach, but not the small intestine, as well as neutrophils and mast cells. It has multiple functions beyond its antimicrobial activity, including promotion of angiogenesis, attraction of leukocyte subsets, and activation of chemokine secretion. Angiogenins are a family of host defence-related ribonucleases, of which at least one is secreted by murine Paneth cells. The differential expression of diverse antimicrobial proteins in the gastrointestinal tract suggests that they occupy distinct functional niches in mucosal innate defence, which holds promise for pharmacological exploitation of their antimicrobial properties.