Abstract
Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.
Highlights
Knee osteoarthritis (KOA) is a degenerative joint disorder that affects all tissues in the knees, while chronic lowgrade inflammation is a major driver of the ongoing joint degeneration [1]
The KOA+Clodronate Liposomes (KOA+CL) group showed a downregulation compared with the KOA group that suggests a depletion of macrophages in the KOA+CL group
Our data showed that the KOA group resulted in a significant upregulation (Figures 1(d)–1(f)) compared with the Normal group, and the KOA+CL group showed a downregulation compared with the KOA group
Summary
Knee osteoarthritis (KOA) is a degenerative joint disorder that affects all tissues in the knees, while chronic lowgrade inflammation is a major driver of the ongoing joint degeneration [1]. Synovial tissue is the soft membrane lining the spaces of knees and contains highly metabolically active cells called synoviocytes which are further separated as synovial macrophages and synovial fibroblasts. These cell types and the synovial tissue as a whole play a key role in normal joint physiology as they facilitate nourishment for chondrocytes and remove the waste products through a synovial fluid [3]. The fact that macrophages are involved in KOA even makes them valid candidates to use in the quantitative assessment of inflammation [5] Synovial fibrosis is another pathological change of synovial tissue characterized by excessive extracellular matrix deposition, which contributes to joint pain and stiffness. Accumulating evidence has demonstrated the critical role of synovial fibroblasts and transforming growth factor-β (TGF-β) in fibrotic response [7, 8]
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