Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100730, China.
Department of Critical Care Medicine, Beijing Jishuitan Hospital, Beijing, 100035, China.
Apoptosis. 2022 Oct;27(9-10):740-750. doi: 10.1007/s10495-022-01740-1. Epub 2022 Jun 27.
Endoplasmic reticulum stress (ERS) has been well documented to participate in the pathophysiological processes of apoptosis in many diseases. Inhibition of ERS ameliorates pathological organ injury. However, the upstream signaling pathways and molecular regulatory mechanisms of which are still unknown. mTOR, an evolutionarily conserved protein kinase, is a key regulator of apoptosis. Hence, in this study, a classical cecal ligation and puncture (CLP) sepsis model was constructed by using the T cell-specific knockout mTOR and TSC1 (Tuberous Sclerosis Complex, the inhibitor of mTOR signaling pathway) mice to explore the underlying signaling pathway and molecular mechanism of host immune imbalance caused by apoptosis in sepsis. We found that mTOR may modulate septic T cell apoptosis by regulating Akt-IRE1-JNK pathway. To further clarify the possible mechanism, the specific inhibitors of PI3K-Akt and IRE1-JNK were used to intervene in mice before/after CLP, respectively. By analyzing the proteins of mTOR-ERS signaling pathway and the expression of apoptosis-related proteins and genes, we found that mTOR mediated the ER stress induced CD4 T cell apoptosis in Septic mice by negatively regulating the Akt-IRE1-JNK-Caspase 3 signaling cascades. These results indicate that mTOR-Akt-IRE1α-JNK signaling pathway mediated the Endoplasmic reticulum stress induced CD4 T cell apoptosis in Septic mice.
内质网应激（ERS）已被充分证明参与许多疾病的细胞凋亡的病理生理过程。抑制 ERS 可改善病理性器官损伤。然而，其上游信号通路和分子调控机制尚不清楚。mTOR 是一种进化上保守的蛋白激酶，是细胞凋亡的关键调节因子。因此，在本研究中，我们使用 T 细胞特异性敲除 mTOR 和 TSC1（mTOR 信号通路的抑制剂）小鼠构建了经典的盲肠结扎穿孔（CLP）脓毒症模型，以探索脓毒症中细胞凋亡引起的宿主免疫失衡的潜在信号通路和分子机制。我们发现 mTOR 可能通过调节 Akt-IRE1-JNK 通路来调节脓毒症 T 细胞凋亡。为了进一步阐明可能的机制，我们分别在 CLP 前后使用 PI3K-Akt 和 IRE1-JNK 的特异性抑制剂对小鼠进行干预。通过分析 mTOR-ERS 信号通路的蛋白和凋亡相关蛋白及基因的表达，我们发现 mTOR 通过负调控 Akt-IRE1-JNK-Caspase 3 信号级联来介导 ER 应激诱导的 CD4 T 细胞凋亡。这些结果表明，mTOR-Akt-IRE1α-JNK 信号通路介导了脓毒症小鼠内质网应激诱导的 CD4 T 细胞凋亡。
