Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl(-) efflux signaling pathway.
Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl(-) efflux signaling pathway.
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DOI：
10.1186/s12967-023-04313-1
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发表时间：
2023-07-08
影响因子：
7.4
通讯作者：
Zhu, Liulong
中科院分区：
文献类型：
--
作者：
Zhang, Zhen;Xie, Shujun;Qian, Jin;Gao, Fengqiang;Jin, Wenjian;Wang, Lingqiao;Yan, Lili;Chen, Hao;Yao, Wangxiang;Li, Maoqiang;Wang, Xuepeng;Zhu, Liulong
关键词：
骨关节炎（OA）是一种炎症性关节炎，其中巨噬细胞驱动的滑膜炎被认为与软骨破坏密切相关，并且可能发生在任何阶段。然而，目前还没有有效的靶点来治疗OA的进展。滑膜巨噬细胞中的含NOD、LRR和pyrin结构域的蛋白3（NLRP 3）炎性体参与病理性炎症过程，靶向其的治疗策略被认为是治疗OA的有效方法。PIM-1激酶作为多种细胞因子信号通路的下游效应子，在炎症性疾病中发挥促炎作用。在这项研究中，我们评估了PIM-1的表达和滑膜巨噬细胞在人OA滑膜中的浸润。在脂多糖（LPS）和不同激动剂如尼日利亚菌素（nigericin）、ATP、尿酸单钠（MSU）和铝盐（Alum）刺激的小鼠和人巨噬细胞中研究PIM-1的作用和机制。采用改良的巨噬细胞条件培养基（CM）诱导的共培养体系，观察其对软骨细胞的保护作用。通过小鼠内侧半月板（DMM）诱导的OA证实了体内治疗效果。PIM-1在人OA滑膜中的表达增加，伴随着滑膜巨噬细胞的浸润。在体外实验中，通过特异性抑制剂SMI-4a抑制PIM-1，迅速抑制小鼠和人巨噬细胞中的NLRP 3炎性小体活化和gasdermin-D（GSDME）介导的焦亡。此外，PIM-1抑制剂特异性地阻断了在组装阶段中的包含CARD（ASC）寡聚化的阿尔茨海默病相关斑点样蛋白。从机制上讲，PIM-1抑制缓解了线粒体活性氧（ROS）/氯离子胞内通道蛋白（CLIC）依赖性Cl−流出信号通路，最终导致ASC寡聚化和NLRP 3炎性小体激活的阻断。此外，PIM-1抑制在改良的共培养系统中显示出软骨保护作用。最后，SMI-4a显著抑制滑膜中PIM-1的表达，并降低DMM诱导的OA模型中的滑膜炎评分和国际骨关节炎研究学会（OARSI）评分。因此，PIM-1代表了一类新的有希望的靶点，作为治疗OA的靶向巨噬细胞中的这些机制，并拓宽了OA治疗策略的道路。在线版本包含补充材料，可通过10.1186/s12967-023-04313-1获得。
Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl− efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA. The online version contains supplementary material available at 10.1186/s12967-023-04313-1.
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影响因子：
2
作者：
Siddiqi S;Sussman MA
通讯作者：
Sussman MA
影响因子：
--
作者：
Clavijo-Cornejo D;Martínez-Flores K;Silva-Luna K;Martínez-Nava GA;Fernández-Torres J;Zamudio-Cuevas Y;Guadalupe Santamaría-Olmedo M;Granados-Montiel J;Pineda C;López-Reyes A
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López-Reyes A
影响因子：
4.6
作者：
Ahn H;Lee GS
通讯作者：
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影响因子：
24.1
作者：
Huang, Bo;Qian, Yufeng;Xia, Dajing
通讯作者：
Xia, Dajing
影响因子：
8
作者：
Chauhan SS;Toth RK;Jensen CC;Casillas AL;Kashatus DF;Warfel NA
通讯作者：
Warfel NA