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.