Immunology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
J Exp Med. 2020 Mar 2;217(3). doi: 10.1084/jem.20190449.
Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.
I 型干扰素（IFN-I）提供有效的抗病毒免疫，但会加剧有害的炎症反应并导致造血干细胞（HSC）衰竭；因此，IFN-I 的表达必须受到严格控制。虽然已经广泛研究了限制 IFN-I 诱导和功能的信号机制，但关于直接作用于 IFN-I 调节区域的转录抑制剂知之甚少。我们发现，NFAT5 是巨噬细胞促炎反应的激活剂，可抑制 Toll 样受体 3 和病毒诱导的巨噬细胞和树突状细胞中 IFN-I 的表达。缺乏 NFAT5 的小鼠在 LCMV 感染时表现出更高的 IFN-I 产生和更好的病毒载量控制，但在系统性 poly(I:C)诱导的炎症下，HSC 的激活加剧。我们确定 IFNβ 是 NFAT5 抑制的主要靶标，通过与 IFNB1 增强子中一个进化上保守的序列结合来拮抗主要的 IFN-I 诱导因子 IRF3，该序列与一个关键的 IRF 位点重叠。这些发现说明了 IFN-I 反应如何通过同时拮抗转录因子来达到平衡。
