| alpha-defensins are innate immune effector molecules. In mice, the only major site of alpha-defensins expression is in Paneth cells, a terminally differentiated secretory cell lineage restricted to the small bowel. Mouse enteric alpha-defensins, termed cryptdins (Crps), are made as inactive precursors and cleaved into biologically active alpha-defensins by matrix metalloproteinase-7 (MMP7) inside Paneth cells. The peptides are released apically as components of dense core granules at mM concentrations in vivo at the point of secretion, although they are microbicidal at low microM concentrations in vitro. Paneth cell alpha-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiota. Here functional alpha-defensins were shown to be abundant in mouse large bowel lumen, demonstrating that alpha-defensins are highly resistant to proteolysis in vivo and redefining the environment in which Paneth cell alpha-defensins may mediate innate immunity to include the large bowel. The colonic localization of alpha-defensins was shown to be independent of the major mucus protein, Muc2, suggesting that intestinal mucus is not required for Paneth cell alpha-defensins to reach the large bowel. Further, the MMP7-/- mouse was shown to have alternatively processed alpha-defensins in the large bowel lumen despite absence of the native convertase, MMP7, and the disordered alpha-defensin proregion was shown to be sensitive to cleavage by other luminal proteases of both host and microbial origin in vitro . Finally, as the large bowel is a site constantly exposed to a high density of anaerobic microorganisms, alpha-defensin bactericidal activity against anaerobes was investigated. Representative alpha-defensins were bactericidal against anaerobic bacteria, and alpha-defensin bactericidal activity against anaerobes and facultative anaerobes was dependent on the oxygen status, test peptide, and target organism species and strain. Taken together, these findings suggest an expanded role for alpha-defensins in enteric innate immunity, imply that effector molecules may be function at sites far from their point of secretion, and highlight the complexity of the interplay between host defense molecules and microbes. |
