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Pyroptosis by NLRP3/caspase-1/gasdermin-D pathway in synovial tissues of rheumatoid arthritis patients
Authors:Xue Zhang  Qiuyuan Wang  Guorui Cao  Manli Luo  Hongli Hou  Chen Yue
Affiliation:1. Department of Rheumatology, Luoyang Orthopaedic Hospital of Henan Province, Luoyang, China;2. Department of Orthopaedic Surgery, Luoyang Orthopaedic Hospital of Henan Province, Luoyang, China
Abstract:We investigated the potential involvement of pyroptosis, a proinflammatory form of regulated cell death, in rheumatoid arthritis (RA). Synovial fluid, synovial tissues and/or serum were compared among 32 patients with RA, 46 patients with osteoarthritis (OA) and 30 healthy controls. Samples were assayed for interleukin (IL)-1β, IL-18 and lactate hydrogenase (LDH). Synovial expression of NLRP3, caspase-1 and cleaved gasdermin D (GSDMD) was assayed using immunohistochemistry and multiplex immunohistochemistry. Patients with RA showed significantly higher levels of IL-1β and IL-18 in synovial fluid than patients with OA, and significantly higher levels of both cytokines in serum than healthy controls. RA was associated with higher levels of LDH in synovial fluid than OA. Among patients with RA, levels of IL-1β, IL-18 and LDH were significantly higher in synovial fluid than in serum, and the levels in synovial fluid positively correlated with disease activity and inflammation. Synovial cells, particularly macrophages, showed upregulation of NLRP3, caspase-1 and cleaved GSDMD in RA compared to OA. Our results implicate pyroptosis in the pathogenesis of RA, perhaps as a driver of local inflammation in joints.
Keywords:caspase-1  gasdermin D  NLRP3  pyroptosis  rheumatoid arthritis  synovial tissue
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