Chapter 16 - Defensins in Enteric Mucosal Immunity

Abstract

The mammalian defensins are composed of three families of cationic, Cys-rich, broad-spectrum microbicides known as α-, β-, and θ-defensins. The α- and β-defensins are ∼4.5kDa cationic peptides with six cysteine residues that form distinctive tridisulfide arrays, and both subfamilies have widespread roles in mucosal immunity. θ-Defensins, ∼2kDa and the only macrocyclic peptides known in the animal kingdom, are potent microbicidal and anti-inflammatory peptides. In the small intestine, α-defensins secreted by Paneth cells in response to cholinergic or infectious stimuli constitute the majority of enteric bactericidal activity. Their roles in providing immunity to oral Salmonella enterica serovar Typhimurium infection and in modulating the composition of the ileal microbiota have been confirmed in vivo in mice. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum stress, autophagy, or apoptosis, contributes to inflammation and dysbiosis, and impairs innate mucosal immunity. In the small intestine, α-defensins secreted by Paneth cells constitute a major source of antimicrobial peptide activity in the small intestine, and analyses of Paneth cell α-defensins have provided compelling and extensive evidence for defensin-mediated mucosal immunity.