Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Michigan, USA.
J Leukoc Biol. 2022 Feb;111(2):379-389. doi: 10.1002/JLB.3A0520-322RR. Epub 2021 Apr 18.
The activation of dendritic cells (DC) during respiratory viral infections is central to directing the immune response and the pathologic outcome. In these studies, the effect of RSV infection on development of ER stress responses and the impact on innate immunity was examined. The upregulation of ER stress was closely associated with the PERK pathway through the upregulation of CHOP in RSV infected DC. The inhibition of PERK corresponded with decreased EIF2a phosphorylation but had no significant effect on Nrf2 in DC, two primary pathways regulated by PERK. Subsequent studies identified that by blocking PERK activity in infected DC an altered ER stress response and innate cytokine profile was observed with the upregulation of IFNβ and IL-12, coincident to the down regulation of IL-1β. When mitochondria respiration was assessed in PERK deficient DC there were increased dysfunctional mitochondria after RSV infection that resulted in reduced oxygen consumption rates (OCR) and ATP production indicating altered cellular metabolism. Use of a CD11c targeted genetic deleted murine model, RSV infection was characterized by reduced inflammation and diminished mucus staining as well as reduced mucus-associated gene gob5 expression. The assessment of the cytokine responses showed decreased IL-13 and IL-17 along with diminished IL-1β in the lungs of PERK deficient infected mice. When PERK-deficient animals were assessed in parallel for lung leukocyte numbers, animals displayed significantly reduced myeloid and activated CD4 and CD8 T cell numbers. Thus, the PERK activation pathway may provide a rational target for altering the severe outcome of an RSV infection through modifying immune responses.
树突状细胞（DC）在呼吸道病毒感染时的激活对于指导免疫反应和病理结果至关重要。在这些研究中，研究了 RSV 感染对内质网应激反应的发展及其对固有免疫的影响。内质网应激的上调与 PERK 途径密切相关，通过上调 RSV 感染的 DC 中的 CHOP。PERK 的抑制与 EIF2a 磷酸化的减少有关，但对 DC 中的 Nrf2 没有显著影响，Nrf2 是 PERK 调节的两个主要途径。随后的研究表明，通过阻断感染 DC 中的 PERK 活性，观察到内质网应激反应和固有细胞因子谱的改变，IFNβ和 IL-12 的上调，同时 IL-1β的下调。当评估 PERK 缺陷的 DC 中的线粒体呼吸时，在 RSV 感染后观察到功能失调的线粒体增加，导致耗氧量（OCR）和 ATP 产生减少，表明细胞代谢发生改变。使用 CD11c 靶向基因敲除的小鼠模型，RSV 感染的特征是炎症减少，粘液染色减少以及粘蛋白相关基因 gob5 表达减少。细胞因子反应的评估显示，PERK 缺陷感染小鼠的肺部中 IL-13 和 IL-17 减少，同时 IL-1β减少。当同时评估 PERK 缺陷动物的肺部白细胞数量时，动物显示出骨髓细胞和活化的 CD4 和 CD8 T 细胞数量明显减少。因此，PERK 激活途径可通过改变免疫反应为改变 RSV 感染的严重后果提供合理的靶标。
