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钙调神经磷酸酶抑制剂通过人单核细胞降低 NFAT 依赖性抗真菌五聚素-3 的表达。

Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes.

机构信息

International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.

Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

出版信息

J Leukoc Biol. 2020 Mar;107(3):497-508. doi: 10.1002/JLB.4VMA0318-138R. Epub 2019 Apr 1.

DOI:10.1002/JLB.4VMA0318-138R
PMID:30934147
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7064969/
Abstract

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-α, 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.

摘要

钙调磷酸酶（CN）抑制剂是有效的临床免疫抑制剂，但会使患者易患潜在致命的真菌感染。本研究检验了以下假设，即 CN 抑制会干扰单核细胞介导的抗真菌免疫防御。我们表明，NFAT 由人单核细胞表达，并通过暴露于真菌配体而被激活。我们使用人单核细胞报告细胞系证实，NFAT 易位强烈激活了靶基因转录。环孢菌素 A 通过抑制 CN-NFAT，显著降低了人单核细胞对模式识别受体配体以及烟曲霉分生孢子的 TNF-α、IL-10 和 MCP-1 蛋白的产生。此外，我们揭示了人类单核细胞在 NFAT 的控制下表达抗真菌蛋白 pentraxin-3。总之，临床 CN 抑制剂有可能干扰新型 NFAT 依赖性 pentraxin-3 途径以及人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的单核细胞介导的抗真菌防御。

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