Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20.
Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor-associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain-containing adaptor inducing interferon (IFN) beta-dependent nuclear factor kappaB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated.
Turer
Emre E
EE
Gastrointestinal Division, Department of Medicine, Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Tavares
Rita M
RM
Mortier
Erwan
E
Hitotsumatsu
Osamu
O
Advincula
Rommel
R
Lee
Bettina
B
Shifrin
Nataliya
N
Malynn
Barbara A
BA
Ma
Averil
A
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006706:Homeostasis; D007249:Inflammation / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D054875:Ubiquitination
D033942:Adaptor Proteins, Vesicular Transport; D003546:Cysteine Endopeptidases; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C513261:Tnfaip3 protein, mouse