Department of Trauma Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Department of Geriatrics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
IUBMB Life. 2022 Nov;74(11):1070-1080. doi: 10.1002/iub.2666. Epub 2022 Aug 4.
Immunosuppression mediated by CD4 T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4 T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4 T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4 T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4 T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4 T cells markedly increased. In addition, sepsis impaired the function of CD4 T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4 T cell apoptosis and maintaining CD4 T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.
CD4 T 细胞凋亡和功能障碍介导的免疫抑制是促进脓毒症进展的关键因素。内质网（ER）应激参与免疫细胞的凋亡和功能障碍。我们旨在研究 ER 应激抑制在脓毒症体外和体内模型中对 CD4 T 细胞的作用。采用脂多糖（LPS）建立脓毒症体外模型，采用盲肠结扎穿孔（CLP）建立脓毒症大鼠模型。LPS 处理或 CLP 后，用 4-PBA、SNJ-1945 和 SP600125 等 ER 应激抑制剂处理细胞或大鼠，并通过磁珠分选获得 CD4 T 细胞。评估 ER 应激抑制剂对 CD4 T 细胞凋亡和功能的影响。在 LPS 刺激或 CLP 后，脓毒症开始时 CD4 T 细胞中 ER 应激及其下游标志物（PERK、eIF2α、IRE-1α、ATF6、ATF4、XBP-1s、GRP78、CHOP 和 p-JNK）的水平升高，同时凋亡的 CD4 T 细胞数量明显增加。此外，脓毒症损害了 CD4 T 细胞的功能，表现为 Th1、Th2、Th17 和 Treg 的比例增加，以及 TNF-α、白细胞介素（IL）-6、IL-4 和 IL-10 的产生增加。然而，ER 应激抑制剂、JNK 和钙蛋白酶抑制剂均降低了 Th1 和 Th17 的诱导，增强了 Th2 和 Treg 的增加，减少了 TNF-α和 IL-6 的产生，增强了 IL-4 和 IL-10 的产生。我们的研究结果表明，ER 应激抑制剂通过减少 CD4 T 细胞凋亡和维持 CD4 T 细胞功能可能发挥保护作用，这可能有助于增强脓毒症患者的免疫功能和不良预后。
