Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production

Systems for protein degradation are essential for tight control of the inflammatory immune response(1,2). Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long- lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation(3-5). However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 ( autophagy-related 16-like 1), which is implicated in Crohn's disease(6,7), regulates endotoxin- induced inflammasome activation in mice. Atg16L1- deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule- associated protein 1 light chain 3 ( LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long- lived proteins are severely impaired in Atg16L1- deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll- like receptor 4 ( refs 8, 9), Atg16L1- deficient macrophages produce high amounts of the inflammatory cytokines IL-1 beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1- deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta ( TRIF)dependent activation of caspase- 1, leading to increased production of IL-1 beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium- induced acute colitis, which is alleviated by injection of anti-IL-1 beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin- induced inflammatory immune response.