Ruxolitinib reduces macrophage pyroptosis in aplastic anaemia
Aplastic anaemia (AA) is a disease that shows complex pathogenesis involving multiple immune factors. While immunosuppressive therapies such as cyclosporine can effectively control AA, they may be ineffective in certain patients or those with relapse. Therefore, new treatments are needed. Among the targets for these treatments, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway regulates inflammatory cytokines and immune activation. Ruxolitinib, a JAK1/2 inhibitor, reduces T-cell activation and the associated inflammatory response and improves AA disease status in mice. However, its mechanism of action is unclear; thus, further research is needed before its clinical use. We previously showed increased pyroptosis in patients with severe AA (SAA) and that macrophage pyroptosis is an important factor in immune activation. The current study investigated the interaction of ruxolitinib with macrophages and whether the drug could treat SAA by improving pyroptosis levels. We induced differentiation of the THP-1 human monocyte cell line into macrophages in vitro and then induced pyroptosis. After constructing a macrophage pyroptosis model, treatment with different concentrations of ruxolitinib was administered. The results showed that ruxolitinib reduced the levels of pyroptosis and inflammatory-related factors. A mouse model of SAA was validated. In conclusion, ruxolitinib may treatment affects SAA by reducing the level of macrophage pyroptosis. Overall design: We induced differentiation into THP-1 macrophages using a human mononuclear THP-1 cell line and induced pyroptosis using ATP and LPS. Three cases each were divided into experimental (RUX+) and control (RUX-) groups according to whether or not they were treated with Lukotinib, and RNA transcriptome sequencing was performed.