The regulation of macrophage polarization by hypoxia-PADI4 coordination in Rheumatoid arthritis
The regulation of macrophage polarization by hypoxia-PADI4 coordination in Rheumatoid arthritis
复制标题
类风湿关节炎中缺氧-PADI4协调对巨噬细胞极化的调节
DOI：
10.1016/j.intimp.2021.107988
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发表时间：
2021-07-29
影响因子：
5.6
通讯作者：
Fan, Lieying
中科院分区：
文献类型：
--
作者：
Cheng, Yu;Si, Yuying;Fan, Lieying
工作背景：缺氧是类风湿关节炎（RA）的一个共同特征，可诱导成纤维细胞样滑膜细胞（FLS）和巨噬细胞中肽基精氨酸脱亚胺酶4（PADI 4）的过度表达。然而，PADI 4及其诱导剂缺氧在巨噬细胞极化调节中的作用仍不清楚。本研究旨在探讨缺氧-PADI 4在RA患者巨噬细胞极化中的作用。方法：收集3例OA患者和6例RA患者的滑膜组织（ST）和滑液（SF）。采用免疫组化和生物素免疫分析法检测ST中M1和M2的分布及SF中细胞因子的分布。在常氧（21%氧）或低氧（3%氧）条件下测定THP-1巨噬细胞和BMDM极化。通过腺病毒载体包被的PADI 4（AdPADI 4）转染巨噬细胞和使用PADI 4抑制剂来确定PADI 4对巨噬细胞的作用。结果：与OA ST相比，RA ST中M1和M2的巨噬细胞极化增加，RA和OA的M1/M2比值分别为1.633 ± 0.1443和2.544 ± 0.4429。RA组M1、M2型细胞因子浓度高于OA组。低氧促进了M1和M2标记基因和蛋白表达的增加。PADI 4表达与M1型基因表达呈正相关，与M2型基因表达无显著性差异。结论：缺氧可使CIA大鼠关节炎模型中M1、M2共极化。缺氧相关的PADI 4负责M1巨噬细胞活化，这意味着可以通过降低PADI 4表达和改善缺氧环境来缓解炎症环境。
Background: Hypoxia, a common feature of rheumatoid arthritis (RA), induces the over-expression of peptidyl arginine deiminase 4 (PADI4) in fibroblast-like synoviocytes (FLSs) and macrophages. However, the roles of PADI4 and its inducer hypoxia in the regulation of macrophage polarization remain unclear. This study aimed to investigate the role of hypoxia-PADI4 for macrophage polarization in RA patients.Methods: Synovial tissue (ST) and synovial fluid (SF) were collected from 3 OA patients and 6 RA patients. The distribution of M1 and M2 in ST and cytokines in SF were examined by immunohistochemical analysis and BioPlex immunoassays. THP-1 macrophages and BMDM polarization were determined under normoxic (21% oxygen) or hypoxic (3% oxygen) conditions. The effects of PADI4 on macrophages were determined by transfection of adenovirus vector-coated PADI4 (AdPADI4) and the use of PADI4 inhibitor. Finally, the roles of PADI4 in joint synovial lesions on macrophage polarization were investigated in collagen-induced arthritis (CIA) rats.Results: We found increased macrophage polarization of M1 and M2 in the RA ST, compared with OA ST. The ratio of M1/M2 for RA and OA was 1.633 +/- 0.1443 and 2.544 +/- 0.4429, respectively. The concentration of M1 and M2-type cytokines was higher in RA than that in OA patients. Hypoxia contributed to the increase of the gene and protein expression of M1 and M2 markers. M1-but not M2-type gene expression showed a positive relationship with PADI4 expression while the level of expression of M2-type genes showed no significant difference. The degree of joint swelling and destruction was effectively alleviated, and the number of macrophages especially M1 decreased in CIA rats after down-regulating PADI4 expression.Conclusion: Hypoxia is responsible for the co-polarization of M1 and M2. Hypoxia-associated PADI4 is responsible for M1 macrophage activation, implying that the inflammatory environment can be eased by decreasing PADI4 expression and improving the hypoxic environment.