1. The integrin CD11b inhibits MSU-induced NLRP3 inflammasome activation in macrophages and protects mice against MSU-induced joint inflammation.
- Author
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Ehirchiou D, Bernabei I, Pandian VD, Nasi S, Chobaz V, Castelblanco M, So A, Martinon F, Li X, Acha-Orbea H, Hugle T, Zhang L, and Busso N
- Subjects
- Animals, Mice, Male, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Macrophages metabolism, CD11b Antigen metabolism, Inflammasomes metabolism, Mice, Knockout, Uric Acid, Arthritis, Gouty chemically induced, Arthritis, Gouty metabolism, Mice, Inbred C57BL
- Abstract
Objective: In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1β. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU., Methods: BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer., Results: We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1β. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1β in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1β by peripheral blood mononuclear cells from healthy donors., Conclusion: Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients., (© 2024. The Author(s).)
- Published
- 2024
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