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Abstract：
Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.
摘要：
目的:骨关节炎(OA)是最突出的慢性关节炎,影响全球超过30亿人。滑膜巨噬细胞,作为免疫细胞，在OA的软骨损伤中起重要作用。因此,调节巨噬细胞对于控制OA的病理变化至关重要。髓样细胞上表达的触发受体2（TREM2），在免疫细胞表面表达，如巨噬细胞和树突状细胞，抑制炎症和调节M2巨噬细胞极化，但在OA滑膜巨噬细胞极化中表现出未知的作用。本研究旨在研究TREM2在OA小鼠巨噬细胞中的表达下调。此外，OA小鼠巨噬细胞中TREM2的表达趋势与极化相关分子的表达有关。结果:我们使用TREM2敲除(TREM2-KO)小鼠观察到TREM2缺乏显著加剧OA小鼠关节炎症反应,从而加速疾病进展。从TREM2-KO小鼠中分离巨噬细胞和软骨细胞并共同培养它们可显着增加软骨细胞凋亡并抑制软骨细胞增殖。Further,TREM2缺乏也显著增强磷脂酰肌醇3-激酶(PI3K)/AKT信号通路激活,增加活化B细胞的核因子κ轻链增强子（NF-κB）信号和C-X-C基序趋化因子配体3（CXCL3）表达。此外，NF-κB信号通路抑制显著抑制OA小鼠关节炎炎症,从而有效缓解TREM2缺乏相关的对软骨细胞的不利影响。值得注意的是,敲除TREM2-KO小鼠巨噬细胞CXCL3显著抑制炎症反应,促进软骨细胞增殖。静脉注射重组TREM2蛋白(solarTREM2,sTREM2)可明显促进巨噬细胞M1向M2的极化,改善OA的关节组织病理和炎症反应。结论：我们的研究表明，TREM2通过NF-κB/CXCL3轴调节促进OA过程中巨噬细胞从M1向M2的极化，从而改善OA的病理状态。
