Abstract
BackgroundRheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis.MethodsWe investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA).ResultsNST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice.ConclusionsThese results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.
Highlights
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregula‐ tion of inflammatory cell death and osteoclastogenesis
We investigated whether the inhibition of receptorinteracting serine/threonine-protein kinase 1 (RIPK1) ameliorates osteoclastogenesis and inflammatory responses in an experimental autoimmune arthritis mouse model with collagen-induced arthritis (CIA)
Administration of NST-1s decreased the arthritis score and showed a protective function in the arthritic tissues of the affected joints (Fig. 1b, c). Proinflammatory cytokines, such as IL-17, IL-1β, IL-6 and tumor necrosis factor (TNF)-α in the arthritic joint were decreased by NST1s treatment (Fig. 2a)
Summary
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregula‐ tion of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-inter‐ acting serine/threonine-protein kinase (RIPK), which plays a role in necroptosis. Rheumatoid arthritis (RA) is a progressive autoimmune polyarthritis disease characterized by severe bone loss and inflammatory cell infiltration in the affected joints. Interleukin (IL)-17 and tumor necrosis factor (TNF)-α are increased in the serum and arthritic synovium in patients with RA [1, 2]. Receptor-interacting serine/threonine-protein kinase (RIPK) is a member of the TNF receptor-I signaling complex that causes necroptosis [9]. Necroptosis is increased in the synovium of animals with experimental autoimmune arthritis [12]
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