IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.
IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.
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DOI：
10.1038/s41467-022-32587-4
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发表时间：
2022-09-08
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
干扰素诱导的跨膜蛋白3（IFITM 3）是一种限制病毒发病机制的限制因子，发挥的免疫调节功能知之甚少。在这里，使用人类和小鼠模型，我们证明IFITM 3促进MyD 88依赖性，TLR介导的IL-6的生产后，暴露于巨细胞病毒（CMV）。IFITM 3还限制响应流感和SARS-CoV-2的IL-6产生。在树突状细胞中，IFITM 3与reticulon 4同种型Nogo-B结合并促进其蛋白酶体降解。我们发现，Nogo-B介导TLR依赖性促炎细胞因子的产生，并促进体内病毒的发病机制，在TLR 2反应的情况下，这一过程涉及TLR 2细胞定位的改变。Nogo-B缺失消除病毒感染的IFITM 3缺陷小鼠中的炎性细胞因子应答和相关疾病因此，我们揭示了Nogo-B作为病毒发病机制的驱动因素，并强调了IFITM 3微调骨髓细胞对病毒刺激的反应性的免疫调节途径。IFITM 3对病毒发病机制的影响知之甚少。在这里，作者表明IFITM 3通过减少响应病毒刺激的Nogo-B介导的炎症来限制巨细胞病毒的发病机制。
Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation. The effect of IFITM3 on viral pathogenesis is poorly understood. Here, the authors show that IFITM3 restricts cytomegalovirus pathogenesis by reducing Nogo-B-mediated inflammation in response to viral stimuli.
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影响因子：
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Fielding, Ceri Alan;Sabberwal, Pragati;Williamson, James C.;Greenwood, Edward J. D.;Crozier, Thomas W. M.;Zelek, Wioleta;Seow, Jeffrey;Graham, Carl;Huettner, Isabella;Edgeworth, Jonathan D.;Price, David A.;Morgan, Paul B.;Ladell, Kristin;Eberl, Matthias;Humphreys, Ian R.;Merrick, Blair;Doores, Katie;Wilson, Sam J.;Lehner, Paul J.;Wang, Eddie C. Y.;Stanton, Richard J.
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