KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis

Abstract

ObjectiveNecroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.MethodsThe plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.ResultsThe plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.ConclusionThese findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

Quizartinib inhibits necroptosis by targeting receptor‐interacting serine/threonine protein kinase 1

“…The prognosis of patients with AML with FLT3 ‐ITD mutation is closely associated with plasma RIPK1 activity and RIPK1 expression in natural killer cells 50 . According to previous reports, many inhibitors of FLT3 inhibit necroptosis 51–56 . Further research is needed to explore the relationship between the FLT3 and RIPK1 pathways.…”

“…50 According to previous reports, many inhibitors of FLT3 inhibit necroptosis. [51][52][53][54][55][56] Further research is needed to explore the relationship between the FLT3 and RIPK1 pathways.…”

Repressive Control of Keratinocyte Cytoplasmic Inflammatory Signaling

“…This could suggest that there is another currently unknown pathway to necroptosis in cells that could be the missing link to understanding how A20 and its partners could both promote and restrict RIPK1-mediated cell death in a context-dependent manner. While potential therapies targeting prominent activators of both types of inflammatory cell death such RIPK1/3 or MLKL have been reported [160,161], those targeting natural repressors such as A20 (see below in Section 4) and related proteins are limited suggesting a potentially interesting avenue of investigation.…”