FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis.
FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis.
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DOI：
10.1038/s41413-022-00211-2
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发表时间：
2022-06-22
期刊：
影响因子：
12.7
通讯作者：
Cai, Daozhang
中科院分区：
文献类型：
--
作者：
Guo, Dong;Lin, Chuangxin;Lu, Yuheng;Guan, Hong;Qi, Weizhong;Zhang, Hongbo;Shao, Yan;Zeng, Chun;Zhang, Rongkai;Zhang, Haiyan;Bai, Xiaochun;Cai, Daozhang
越来越多的证据表明，脂肪因子在类风湿关节炎（RA）的发生发展中起着至关重要的作用。脂肪酸结合蛋白4（FABP4）是一种新的脂肪因子，调节炎症和血管生成，已被广泛研究的各种器官和疾病。然而，FABP4对RA的影响仍不清楚。在这里，我们发现，FABP4表达上调滑膜M1极化的巨噬细胞在RA。FABP4的增加促进滑膜炎、血管生成和软骨降解，从而加剧体内和体外RA进展，而BMS 309403（FABP4抑制剂）和阿格列汀（二肽基肽酶4抑制剂）抑制小鼠血清和滑膜M1极化巨噬细胞中的FABP4表达，从而缓解RA进展。进一步的研究表明，通过骨髓谱系中特异性的TSC 1缺失对雷帕霉素复合物1（mTORC 1）的哺乳动物靶标的组成性激活调节巨噬细胞中的FABP4表达，从而加剧小鼠中的RA进展。相比之下，通过在脑中富集的ras同源物（Rheb 1）破坏特异性地在髓系中抑制mTORC 1减少巨噬细胞中的FABP4表达以减弱小鼠中的RA发展。我们的研究结果确定了FABP4在RA滑膜炎、血管生成和软骨降解中的重要作用，FABP4由M1极化的巨噬细胞分泌。BMS309403和阿格列汀抑制滑膜M1极化巨噬细胞中的FABP4表达，以缓解RA发展。因此，FABP4可能代表RA治疗的潜在靶点。
Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis (RA). Fatty acid-binding protein 4 (FABP4), a novel adipokine that regulates inflammation and angiogenesis, has been extensively studied in a variety of organs and diseases. However, the effect of FABP4 on RA remains unclear. Here, we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA. The increase in FABP4 promoted synovitis, angiogenesis, and cartilage degradation to exacerbate RA progression in vivo and in vitro, whereas BMS309403 (a FABP4 inhibitor) and anagliptin (dipeptidyl peptidase 4 inhibitor) inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression. Further studies showed that constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice. In contrast, inhibition of mTORC1 by ras homolog enriched in brain (Rheb1) disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice. Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis, angiogenesis, and cartilage degradation in RA. BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development. Hence, FABP4 may represent a potential target for RA therapy.
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