Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes
Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes
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DOI：
10.1002/jlb.4vma0318-138r
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发表时间：
2020-03-01
影响因子：
5.5
通讯作者：
Fric, Jan
中科院分区：
文献类型：
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作者：
Bendickova, Kamila;Tidu, Federico;Fric, Jan
钙调神经磷酸酶(CN)抑制剂是有效的临床免疫抑制剂，但会使患者容易受到潜在的致命真菌感染。本研究验证了CN抑制干扰单核细胞介导的抗真菌免疫防御的假说。我们发现NFAT是由人类单核细胞表达的，并通过暴露于真菌配体而被激活。我们利用人单核细胞报告细胞系证实了NFAT易位有效地激活了靶基因的转录。环孢菌素A抑制CN-NFAT显著减少单核细胞对模式识别受体配体和烟曲霉分生孢子产生的TNF-α、IL-10和MCP-1蛋白的反应。此外，我们还发现，在NFAT的控制下，人单核细胞表达抗真菌蛋白五角蛋白-3。总之，临床上的CN抑制剂有可能干扰新的NFAT依赖的五星蛋白-3途径以及人类单核细胞中抗真菌细胞因子的产生，从而阻碍免疫抑制患者单核细胞对真菌感染的防御。
Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-alpha, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.