Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, United States.
Arthritis Res Ther. 2024 Jun 11;26(1):119. doi: 10.1186/s13075-024-03350-5.
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.
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.
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.
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.
在痛风中，单钠尿酸盐晶体被巨噬细胞摄取，触发 NLRP3 炎性体的激活和 IL-1β 的成熟。本研究旨在探讨整合素 CD11b 在 MSU 刺激的巨噬细胞炎性小体激活中的作用。
用 MSU 晶体体外刺激 WT 和 CD11b KO 小鼠的 BMDM。收集细胞上清液，通过酶联免疫吸附试验和 Western blot 方法评估炎性细胞因子的表达。通过关节内注射 MSU 晶体，研究整合素 CD11b 在体内 MSU 诱导的痛风性关节炎中的作用。通过 Seahorse 细胞外通量分析仪测量 BMDM 的实时细胞外酸化率和耗氧量。
我们证明，CD11b 缺陷小鼠发展为痛风性关节炎加重，关节内白细胞募集增加，血清中 IL-1β 水平升高。在巨噬细胞中，CD11b 的基因缺失诱导了巨噬细胞代谢从氧化磷酸化向糖酵解的转变，从而降低了细胞内 ATP 的总体生成。在 MSU 刺激下，CD11b 缺陷型巨噬细胞表现出 IL-1β 的分泌加剧。用 CD11b 激动剂 LA1 处理野生型巨噬细胞，可抑制 MSU 诱导的 IL-1β 释放，并减轻实验性痛风性关节炎的严重程度。重要的是，LA1 对健康供体的外周血单核细胞也有效，因为它抑制了 MSU 诱导的外周血单核细胞释放 IL-1β。
我们的数据确定了 CD11b 整合素作为主要的细胞膜受体，通过 MSU 晶体调节巨噬细胞中的 NLRP3 炎性体激活，这可能是治疗人类痛风性关节炎的潜在治疗靶点。
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