Defects in autophagy enhance IL-1beta inflammation
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Loss of the autophagy protein Atg16L1 enhances endotoxin-induced
IL-1beta production.
Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda
T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O,
Yoshimori T, Akira S.
Laboratory of Host Defense, WPI Immunology Frontier Research Center,
Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Systems for protein degradation are essential for tight control of the
inflammatory immune response. 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. 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, 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-1beta
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-1beta. Mice lacking Atg16L1 in haematopoietic
cells are highly susceptible to dextran sulphate sodium-induced acute
colitis, which is alleviated by injection of anti-IL-1beta 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.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 18849965