Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl− efflux signaling pathway

• DOI: 10.1186/s12967-023-04313-1
• Publication Date: 2023-07-08T07:02:12Z
• Authors: Zhen Zhang; Shujun Xie; Jin Qian; Fengqiang Gao; Wenjian Jin; Lingqiao Wang; Lili Yan; Hao Chen; Wangxiang Yao; Maoqiang Li; Xuepeng Wang; Liulong Zhu
• Keywords: Pyroptosis; NALP3; Proinflammatory cytokine; Pyrin domain

Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, an inflammatory arthritis. However, there are no effective targets cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome synovial macrophages participates pathological process treatment strategies targeting it be approach for PIM-1 kinase, as a downstream effector many cytokine signaling pathways, plays pro-inflammatory role disease.In this study, we evaluated expression infiltration human OA synovium. effects mechanism were investigated mice stimulated by lipopolysaccharide (LPS) different agonists such nigericin, ATP, Monosodium urate (MSU), Aluminum salt (Alum). protective on chondrocytes assessed modified co-culture system induced macrophage condition medium (CM). therapeutic effect vivo was confirmed medial meniscus (DMM)-induced mice.The increased synovium accompanied macrophages. In vitro experiments, suppression SMI-4a, specific inhibitor, rapidly inhibited NLRP3 activation gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, inhibition specifically blocked apoptosis-associated speck-like containing CARD (ASC) oligomerization assembly stage. Mechanistically, alleviated mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux pathway, eventually resulted blockade ASC activation. showed chondroprotective system. Finally, SMI-4a significantly suppressed reduced scores Research Society International (OARSI) score DMM-induced model.Therefore, represented new class promising target these mechanisms widened road