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  • Title: Monosodium urate crystal interleukin-1β release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation.
    Author: Rossato MF, Hoffmeister C, Trevisan G, Bezerra F, Cunha TM, Ferreira J, Silva CR.
    Journal: Rheumatology (Oxford); 2020 Jan 01; 59(1):233-242. PubMed ID: 31298290.
    Abstract:
    OBJECTIVE: The present study aimed to elucidate the mechanisms involved in MSU-induced IL-1β release in a rodent animal model of acute gout arthritis. METHODS: Painful (mechanical and thermal hypersensitivity, ongoing pain and arthritis score) and inflammatory (oedema, plasma extravasation, cell infiltration and IL-1β release) parameters were assessed several hours after intra-articular injection of MSU (100 µg/articulation) in wild-type or knockout mice for Toll-like receptor 4 (TLR4), inducible nitric oxide synthase (iNOS), transient receptor potential (TRP) V1 and the IL-1 receptor (IL-1R). Also, wild-type animals were treated with clodronate, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) (TLR4 antagonist), spleen tyrosine kinase (SYK) inhibitor (iSYK), aminoguanidine (AMG, an iNOS inhibitor) or SB366791 (TRPV1 antagonist). Nitrite/nitrate and IL-1β levels were measured on the synovial fluid of wild-type mice, 2 h after intra-articular MSU injections, or medium from macrophages stimulated for MSU (1000 μg) for 2 h. RESULTS: Intra-articular MSU injection caused robust nociception and severe inflammation from 2 up to 6 h after injection, which were prevented by the pre-treatment with clodronate, LPS-RS, iSYK, AMG and SB366791, or the genetic ablation of TLR4, iNOS, TRPV1 or IL-1R. MSU also increased nitrite/nitrate and IL-1β levels in the synovial fluid, which was prevented by clodronate, LPS-RS, iSYK and AMG, but not by SB366791. Similarly, MSU-stimulated peritoneal macrophages released nitric oxide, which was prevented by LPS-RS, iSYK and AMG, but not by SB366791, and released IL-1β, which was prevented by LPS-RS, iSYK, AMG and SB366791. CONCLUSION: Our data indicate that MSU may activate TLR4, SYK, iNOS and TRPV1 to induce the release of IL-1β by macrophages, triggering nociception and inflammation during acute gout attack.
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