Cyclosporine A Regulates Influenza A Virus-induced Macrophages Polarization and Inflammatory Responses by Targeting Cyclophilin A.
Cyclosporine A Regulates Influenza A Virus-induced Macrophages Polarization and Inflammatory Responses by Targeting Cyclophilin A.
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DOI：
10.3389/fimmu.2022.861292
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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环孢素A （Cyclosporine A, CsA）是一种免疫抑制药物，可抑制T细胞反应，广泛应用于移植。其免疫抑制作用与它与广泛分布于不同细胞类型的亲环蛋白A （CypA）的结合密切相关。CsA也调节先天免疫细胞的功能，但其机制尚不清楚。在此，我们研究了CsA在甲型流感病毒感染小鼠和小鼠骨髓源性巨噬细胞中调控巨噬细胞极化的作用。CsA下调促炎细胞因子表达，上调抗炎细胞因子表达。机械上，CsA减少巨噬细胞向促炎M1表型的极化，增加巨噬细胞向抗炎M2表型的极化。进一步研究表明，CsA调节巨噬细胞极化相关的IFN-γ/STAT1和IL-4/STAT6信号通路。同时，当CypA缺失时，CsA的这些作用都被消除，提示CsA调节巨噬细胞极化和炎症反应依赖于其与CypA的结合。总的来说，这些结果揭示了CsA通过巨噬细胞极化开关来减轻iav诱导的炎症反应的关键机制。
Cyclosporine A (CsA) is an immunosuppressive drug that suppresses T cell responses and is broadly used in transplantation. Its immunosuppressive action is closely linked to its binding of cyclophilin A (CypA), which widely distributed in different cell types. CsA also regulates the functions of innate immune cells, but the mechanism remains elusive. Here, we investigate the role of CsA in regulating macrophages polarization in influenza A virus-infected mice and mouse bone marrow-derived macrophages. CsA downregulates pro-inflammatory cytokines expression and upregulates anti-inflammatory cytokines expression. Mechanically, CsA decreases the polarization of macrophages into pro-inflammatory M1 phenotype and increases the polarization of macrophages into anti-inflammatory M2 phenotype. Further studies show that CsA regulates macrophages polarization-associated IFN-γ/STAT1 and IL-4/STAT6 signaling pathways. Meanwhile, all these roles of CsA are eliminated when CypA is absent, suggesting that CsA regulates macrophages polarization and inflammatory responses depend on its binding to CypA. Collectively, these results reveal a crucial mechanism of CsA in attenuating IAV-induced inflammatory responses by a switch in macrophages polarization.