MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals.
While it is known that monosodium urate (MSU) crystals cause the disease gout, the mechanism by which these crystals stimulate this inflammatory condition has not been clear. Here we find that the Toll/IL-1R (TIR) signal transduction adaptor myeloid differentiation primary response protein 88 (MyD88) is required for acute gouty inflammation. In contrast, other TIR adaptor molecules, TIRAP/Mal, TRIF, and TRAM, are not required for this process. The MyD88-dependent TLR1, -2, -4, -6, -7, -9, and -11 and IL-18 receptor (IL-18R) are not essential for MSU-induced inflammation. Moreover, MSU does not stimulate HEK cells expressing TLR1-11 to activate NF-kappaB. In contrast, mice deficient in the MyD88-dependent IL-1R showed reduced inflammatory responses, similar to those observed in MyD88-deficient mice. Similarly, mice treated with IL-1 neutralizing antibodies also showed reduced MSU-induced inflammation, demonstrating that IL-1 production and IL-1R activation play essential roles in MSU-triggered inflammation. IL-1R deficiency in bone marrow-derived cells did not affect the inflammatory response; however, it was required in non-bone marrow-derived cells. These results indicate that IL-1 is essential for the MSU-induced inflammatory response and that the requirement of MyD88 in this process is primarily through its function as an adaptor molecule in the IL-1R signaling pathway.
Chen
Chun-Jen
CJ
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Shi
Yan
Y
Hearn
Arron
A
Fitzgerald
Kate
K
Golenbock
Douglas
D
Reed
George
G
Akira
Shizuo
S
Rock
Kenneth L
KL
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D006073:Gout / Q000139:chemically induced / Q000276:immunology*; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology; D014527:Uric Acid / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014527:Uric Acid