Department of Critical Care Medicine State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.
Mediators Inflamm. 2024 Jul 25;2024:4233439. doi: 10.1155/2024/4233439. eCollection 2024.
Sepsis has been the leading cause of death in ICU patients. CD4+ T cells are the mainstay of the body's immune system, and the depletion of CD4+ T cells in sepsis is of great concern. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a negative immunomodulator for T cell activation and degradation through the autophagy-lysosome pathway. Mammalian target of rapamycin (mTOR) is the most classical upstream regulator of autophagy. With a mouse model of sepsis through cecal ligation and puncture (CLP), T cell specific-mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice, and bafilomycin A1, a specific autophagosome-lysosome (A-L) fusion inhibitor, we primarily proved that mTOR could modulate the expression and accumulation of CTLA4 by regulating the onset process of autophagy such as A-L fusion. Given such a regulatory relationship, targeting mTOR could provide new light to improve immune function in sepsis, and the prospect of using rapamycin in the clinic would be worth exploring further.
脓毒症一直是 ICU 患者死亡的主要原因。CD4+ T 细胞是人体免疫系统的主要支柱，脓毒症中 CD4+ T 细胞的耗竭令人十分关注。细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）是一种通过自噬-溶酶体途径对 T 细胞激活和降解起负调节作用的免疫调节剂。雷帕霉素靶蛋白（mTOR）是自噬最经典的上游调控因子。通过盲肠结扎和穿孔（CLP）建立脓毒症小鼠模型、T 细胞特异性 mTOR/结节性硬化复合物 1（TSC1）敲除小鼠以及自噬体-溶酶体（A-L）融合抑制剂巴弗洛霉素 A1，我们初步证明了 mTOR 可以通过调节自噬体-溶酶体融合等起始过程来调节 CTLA4 的表达和积累。鉴于这种调控关系，靶向 mTOR 可能为改善脓毒症的免疫功能提供新的思路，雷帕霉素在临床上的应用前景值得进一步探索。
