MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals
Chun-Jen Chen, Yan Shi, Arron Hearn, Kate Fitzgerald, Douglas Golenbock, George Reed, Shizuo Akira, Kenneth L. Rock
Chun-Jen Chen, Yan Shi, Arron Hearn, Kate Fitzgerald, Douglas Golenbock, George Reed, Shizuo Akira, Kenneth L. Rock
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Research Article Immunology

MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals

Abstract

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-κB. 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.

Authors

Chun-Jen Chen, Yan Shi, Arron Hearn, Kate Fitzgerald, Douglas Golenbock, George Reed, Shizuo Akira, Kenneth L. Rock

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Figure 7

The role of IL-1 in MSU-induced inflammation.

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The role of IL-1 in MSU-induced inflammation. (A) C57BL/6 mice were admi...
(A) C57BL/6 mice were administered i.v. with anti–IL-1 antibodies or PBS (vehicle). Thirty minutes later, the treated mice and IL-1R–/– mice were challenged i.p. with MSU crystals. C57BL/6 mice challenged with PBS served as negative controls. At 6 hours after MSU challenge, neutrophil numbers in the PECs were determined (n = 4). *P < 0.01 versus control (vehicle). (B) C57BL/6, MyD88–/–, and IL-1R–/– mice were challenged i.p. with 3 mg of MSU crystals (in PBS). C57BL/6 mice challenged with PBS served as negative controls. At 6 hours after MSU challenge, IL-1β concentration in the peritoneal lavage fluids were determined by ELISA (n = 5). Data shown are representative of 2 experiments in A and 3 experiments in B. *P < 0.01 versus control (C57BL/6).