Department of Immunology and Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, 98109, USA.
Department of Basic Sciences, Touro University Nevada, Henderson, NV, 89014, USA.
Nat Commun. 2019 Aug 13;10(1):3649. doi: 10.1038/s41467-019-11250-5.
RIG-I-Like Receptors (RLRs) RIG-I, MDA5, and LGP2, are vital pathogen recognition receptors in the defense against RNA viruses. West Nile Virus (WNV) infections continue to grow in the US. Here, we use a systems biology approach to define the contributions of each RLR in the innate immune response to WNV. Genome-wide RNAseq and bioinformatics analyses of macrophages from mice lacking either RLR reveal that the RLRs drive distinct immune gene activation and response polarization to mediate an M1/inflammatory signature while suppressing the M2/wound healing phenotype. While LGP2 functions to modulate inflammatory signaling, RIG-I and MDA5 together are essential for M1 macrophage polarization in vivo and the control of WNV infection through potential downstream control of ATF4 and SMAD4 to regulate target gene expression for cell polarization. These analyses reveal the RLR-driven signature of macrophage polarization, innate immune protection, and immune programming against WNV infection.
模式识别受体（RLRs）RIG-I、MDA5 和 LGP2 是防御 RNA 病毒的重要病原体识别受体。西尼罗河病毒（WNV）在美国的感染继续增加。在这里，我们使用系统生物学方法来定义每个 RLR 在先天免疫反应中对 WNV 的贡献。从小鼠巨噬细胞中缺失 RLR 的全基因组 RNAseq 和生物信息学分析表明，RLRs 驱动不同的免疫基因激活和反应极化，以介导 M1/炎症表型，同时抑制 M2/伤口愈合表型。虽然 LGP2 具有调节炎症信号的作用，但 RIG-I 和 MDA5 共同对于体内 M1 巨噬细胞极化以及通过潜在的下游 ATF4 和 SMAD4 控制来调节细胞极化的靶基因表达来控制 WNV 感染是必不可少的。这些分析揭示了 RLR 驱动的巨噬细胞极化、先天免疫保护和针对 WNV 感染的免疫编程特征。
