Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK.
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK.
Nat Commun. 2022 Sep 8;13(1):5294. doi: 10.1038/s41467-022-32587-4.
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.
干扰素诱导跨膜蛋白 3（IFITM3）是一种限制因子，可限制病毒的发病机制，并发挥作用尚不明确的免疫调节功能。在这里，我们使用人类和小鼠模型证明，IFITM3 可促进巨细胞病毒（CMV）暴露后 MyD88 依赖性、TLR 介导的 IL-6 产生。IFITM3 还可限制流感和 SARS-CoV-2 引起的 IL-6 产生。在树突状细胞中，IFITM3 与 reticulon 4 同种型 Nogo-B 结合并促进其蛋白酶体降解。我们揭示了 Nogo-B 介导 TLR 依赖性促炎细胞因子产生，并在体内促进病毒发病机制，在 TLR2 反应的情况下，该过程涉及 TLR2 细胞定位的改变。Nogo-B 缺失可消除病毒感染的 IFITM3 缺陷型小鼠中的炎症细胞因子反应和相关疾病。因此，我们发现 Nogo-B 是病毒发病机制的驱动因素，并强调了一种免疫调节途径，其中 IFITM3 可微调髓样细胞对病毒刺激的反应性。
