The Flavonoid Naringenin Alleviates Collagen-Induced Arthritis through Curbing the Migration and Polarization of CD4(+) T Lymphocyte Driven by Regulating Mitochondrial Fission.
The Flavonoid Naringenin Alleviates Collagen-Induced Arthritis through Curbing the Migration and Polarization of CD4(+) T Lymphocyte Driven by Regulating Mitochondrial Fission.
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类黄酮柚皮素通过抑制由调节线粒体裂变驱动的 CD4(+) T 淋巴细胞的迁移和极化来减轻胶原诱导的关节炎。
DOI：
10.3390/ijms24010279
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发表时间：
2022-12-23
影响因子：
5.6
通讯作者：
Wen, Cheng-Ping
中科院分区：
文献类型：
--
作者：
Jiang, Yue-Peng;Wen, Jun-Jun;Zhao, Xiao-Xuan;Gao, Yuan-Cheng;Ma, Xiao;Song, Si-Yue;Jin, Yan;Shao, Tie-Juan;Yu, Jie;Wen, Cheng-Ping
关键词：
类风湿关节炎(RA)是一种进行性自身免疫性疾病。由于局部的浸润和关节的损伤，活化的CD4+T细胞在RA的进展中起着至关重要的作用。然而，具体的监管机制令人困惑，这使得对RA的有效管理变得令人沮丧。本研究旨在探讨线粒体分裂对CD4+T细胞极化和迁移的影响以及NAR的调控机制，为RA的治疗靶点和新策略提供启示。建立胶原性关节炎(CIA)大鼠模型，随机给予生理盐水或柚皮苷(NAR，10 mg/kg、20 mg/kg、50 mg/kg，ip)。每天一次，在初次免疫第42天实施安乐死之前。观察两组患者的疼痛行为、关节指数评分、滑膜浸润的CD4+T细胞数和炎症因子的变化。在体外，取各组小鼠脾组织中的CD4+T淋巴细胞。此外，在含有C-X-C基序趋化因子配体12(CXCL12)的细胞培养液中分别加入线粒体分裂抑制因子1(Mdivi-1)或NAR，以诱导CD4+T淋巴细胞。以F-肌动蛋白和肌球蛋白轻链Ser19(PMLC S19)磷酸化的免疫荧光强度来评价CD4+T细胞的极化能力，通过线粒体膜外膜转位酶20(线粒体标记TOM20)和细胞间黏附分子1(尾足标记ICAM1)的共定位分析确定线粒体的分布。用Western印迹和免疫荧光方法检测线粒体动力蛋白相关蛋白1(Drp1)和线粒体分裂蛋白1(Fis1)。本研究表明，大剂量NAR(50 mg/kg，i.p.)能明显减轻CIA组大鼠的疼痛行为和关节指数评分，降低血清IL-6和肿瘤坏死因子α水平，减少滑膜中α+T细胞的数量。NAR(50 mg/kg，i.p.)抑制CIA模型小鼠脾CD4+T淋巴细胞极化，减少尾足线粒体重分布，抑制Drp1和Fis1的表达。此外，体外实验证实，NAR减少了线粒体的分裂，进而抑制了CXCL12诱导的CD4+T淋巴细胞的极化和迁移。结果表明，类黄酮类NAR能有效干扰线粒体的分裂，从而抑制滑膜中CD4+T细胞的极化和迁移，是一种有前途的治疗RA的药物。
Rheumatoid arthritis (RA) is a progressive autoimmune disease. Due to local infiltration and damage to the joints, activated CD4+ T cells play a crucial role in the progression of RA. However, the exact regulatory mechanisms are perplexing, which makes the effective management of RA frustrating. This study aimed to investigate the effect of mitochondria fission on the polarization and migration of CD4+ T cells as well as the regulatory mechanism of NAR, so as to provide enlightenment on therapeutic targets and novel strategies for the treatment of RA. In this study, a collagen-induced arthritis (CIA) model was established, and rats were randomly given saline or naringenin (NAR, 10 mg/kg, 20 mg/kg, 50 mg/kg, i.p.) once a day, before being euthanized on the 42nd day of primary immunization. The pain-like behavior, articular index scores, account of synovial-infiltrated CD4+ T cells, and inflammatory factors were investigated in each group. In vitro, spleen CD4+ T lymphocytes were derived from each group. In addition, mitochondrial division inhibitor 1 (Mdivi-1) or NAR was added to the cell medium containing C-X-C motif chemokine ligand 12 (CXCL12) in order to induce CD4+ T lymphocytes, respectively. The polarization capacity of CD4+ T cells was evaluated through the immunofluorescence intensity of the F-actin and myosin light chain phosphorylated at Ser19 (pMLC S19), and the mitochondrial distribution was determined by co-localization analysis of the translocase of outer mitochondrial membrane 20 (TOM20, the mitochondrial marker) and intercellular adhesion molecule 1 (ICAM1, the uropod marker). The mitochondrial fission was investigated by detecting dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1) using Western blot and immunofluorescence. This study revealed that high-dose NAR (50 mg/kg, i.p.) alleviated pain-like behavior and articular index scores, reduced the serum level of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and accounted for CD4+ T lymphocytes that infiltrated into the synovial membrane of the CIA group. Meanwhile, NAR (50 mg/kg, i.p.) suppressed the polarization of spleen CD4+ T lymphocytes, reduced the redistribution of mitochondria in the uropod, and inhibited the expression of Drp1 and Fis1 in the CIA model. Furthermore, the in vitro experiments confirmed that NAR reduced mitochondrial fission, which in turn inhibited the CXCL12-induced polarization and migration of CD4+ T lymphocytes. Our results demonstrated that the flavonoid NAR was a promising drug for the treatment of RA, which could effectively interfere with mitochondrial fission, thus inhibiting the polarization and migration of CD4+ T cells in the synovial membrane.
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影响因子：
1.2
作者：
Flaherty, Stephanie;Reynolds, Joseph M.
通讯作者：
Reynolds, Joseph M.
影响因子：
5.6
作者：
Li, Yi-Rong;Chen, Der-Yuan;Lin, Chi-Chen
通讯作者：
Lin, Chi-Chen
DOI：
10.1096/fj.202100067r
发表时间：
2021-06
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Adebayo M;Singh S;Singh AP;Dasgupta S
通讯作者：
Dasgupta S
影响因子：
64.8
作者：
Kleele, Tatjana;Rey, Timo;Manley, Suliana
通讯作者：
Manley, Suliana
影响因子：
3.7
作者：
Galligan CL;Siebert JC;Siminovitch KA;Keystone EC;Bykerk V;Perez OD;Fish EN
通讯作者：
Fish EN