Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis.
Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis.
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DOI：
10.1038/s41419-022-05065-4
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发表时间：
2022-07-14
影响因子：
9
通讯作者：
Du, Yan
中科院分区：
文献类型：
--
作者：
Cheng, Qi;Chen, Mo;Liu, Mengdan;Chen, Xin;Zhu, Lingjiang;Xu, Jieying;Xue, Jing;Wu, Huaxiang;Du, Yan
滑膜成纤维细胞(SFS)的异常激活在类风湿关节炎(RA)发病中起重要作用，其机制尚不清楚。本研究旨在全面系统地探讨信号素5A在类风湿关节炎中异常激活SF的机制。在这里，我们发现类风湿关节炎患者滑液和滑膜组织中信号素5A的水平显著高于骨关节炎患者。我们进一步发现RA SFS与OA SFS相比，Plexin-A1的表达水平和蛋白丰度均升高，而Plexin-B3的表达无显著差异。RA滑液中信号素5A的增加主要来源于CD68+的滑膜巨噬细胞，这种增加导致信号素5A与其受体结合增加，从而促进细胞因子的分泌、增殖和迁移，减少细胞凋亡。此外，在小干扰RNA敲除Plexin-A1和Plexin-B3后，Semaphorin 5A促进SFS活化(细胞因子分泌、细胞增殖和迁移)和减少凋亡的作用被显著取消。转录组测序和蛋白质芯片检测表明，Semaphorin 5A激活了PI3K/AKT/mTOR信号通路，抑制了铁下垂。透射电子显微镜观察结果显示，Semaphorin 5A能显著消除铁下垂诱导剂RSL3诱导的SFS线粒体减少、膜密度增加和脊裂裂的现象。机制上，Semaphorin 5A通过激活PI3K/AKT/mTOR信号通路，促进Gpx4表达和SREBP1/SCD-1信号转导，从而抑制RA SFS的下垂。综上所述，我们的研究提供了第一个证据，证明RA滑液中信号素5A的升高通过PI3K/AKT/mTOR信号通路抑制铁性下垂，从而促进SF的激活。
Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68+ synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
影响因子：
17.1
作者：
Kuo, David;Ding, Jennifer;Donlin, Laura T.
通讯作者：
Donlin, Laura T.
影响因子：
30.5
作者：
Zhang, Fan;Wei, Kevin;Utz, Paul J.
通讯作者：
Utz, Paul J.
DOI：
10.1158/1541-7786.mcr-18-0055
发表时间：
2018-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Lee YS;Lee DH;Choudry HA;Bartlett DL;Lee YJ
通讯作者：
Lee YJ