最新细胞功能及机制文献分享败血症是由宿主对感染反应失调引起的危及生命的器官功能障碍性疾病，并且其仍然是重症监护病房的主要医学挑战之一。包括巨噬细胞、树突状细胞（DCs）和T淋巴细胞在内的脾白细胞数量减少的程度是败血症严重程度以及败血症和休克患者预后的关键性决定因素。SESN2是一种进化上高度保守的蛋白质，与细胞的各种反应密切相关，可维持内环境稳态。然而，SESN2在败血症背景下调节DCs细胞焦亡的潜在作用和相关机制尚不清楚。2021年6月11日，中国人民解放军总医院暨中国人民解放军医学院姚咏明团队在Cellular and Molecular Life Sciences上发表了题为“Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells”的研究论文。在本研究中，团队证明SESN2对抑制NLRP3炎症小体过度活化、减少CASP-1依赖性细胞焦亡和稳定内质网（ER）至关重要，其可改善败血症结果。此项研究对探索治疗败血症并发症的新型潜在治疗靶点具有重要意义。DCs是最重要的专职抗原呈递细胞，在启动适应性免疫反应中起着关键作用，已有研究证明，DCs的消耗发生在败血症早期阶段，并且消耗的程度与败血症患者致命结果密切相关。细胞焦亡是程序性坏死细胞死亡的一种亚型，它通过促进至少一种细胞溶质炎性体的激活来诱导炎症，NLRP3炎症小体是表征最全面的经典炎症小体，其可活化caspase-1（CASP-1）。之前有报道称，包括ER应激（ERS）在内的几种信号通路均参与了炎症小体的激活，过度的ERS是导致DCs细胞凋亡和功能障碍的主要原因，在败血症背景下，这会导致宿主免疫系统的破坏。研究显示，SESN2在败血症中科作为抗炎、抗细胞凋亡和抗氧化靶标而发挥保护作用。基于上述研究背景，团队旨在深入研究SESN2在败血症中调节NLRP3-CASP-1介导的DCs细胞焦亡的保护作用和机制。团队通过在盲肠结扎和穿刺（CLP）诱导的败血症小鼠模型中收集脾脏DCs，发现模型小鼠出现明显细胞焦亡的形态学特征，例如膜塌陷、细胞质肿胀、核周染色质聚集、细胞质空泡化以及ER和线粒体肿胀，并且NLRP3与CASP-1水平明显上升。机制上，SESN2经PERK-ATF4-CHOP通路被上调，而ATF4的过度活化可导致CHOP表达的明显升高。此外，CHOP可激活NLRP3炎症小体并促进pro-CASP-1活化为CASP-1，之后，CASP-1裂解GSDMD的N端片段，然后GSDMD-N在质膜中寡聚化，从而导致细胞内容物的释放和细胞焦亡。再者，CASP-1激活导致IL-1β和IL-18的成熟以及细胞因子（IL-6、HMGB1、TNF-α等）的释放，从而诱发炎症反应、免疫功能障碍，甚至细胞死亡。最后，SESN2的上调可能会减少蛋白质翻译，减弱ERS，随后通过PERK-ATF4-CHOP途径抑制NLRP3炎性体激活，控制继发于败血症的过度炎症反应和细胞焦亡。图 SESN2维持ERS稳态，抑制细胞焦亡和延长NLRP3炎症小体激活机制示意图。期刊及DOI号Cell Mol Life Sci. 2021 Nov 6. doi: 10.1007/s00018-021-03970-z.题目Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells摘要Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in the cellular response to various stresses and has been confirmed to maintain the homeostasis of the internal environment. However, the potential effects of SESN2 in regulating dendritic cells (DCs) pyroptosis in the context of sepsis and the related mechanisms are poorly characterized. In this study, we found that SESN2 was capable of decreasing gasdermin D (GSDMD)-dependent pyroptosis of splenic DCs by inhibiting endoplasmic reticulum (ER) stress (ERS)-related nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated ASC pyroptosome formation and caspase-1 (CASP-1) activation. Furthermore, SESN2 deficiency induced NLRP3/ASC/CASP-1-dependent pyroptosis and the production of proinflammatory cytokines by exacerbating the PERK–ATF4–CHOP signaling pathway, resulting in an increase in the mortality of septic mice, which was reversed by inhibiting ERS. These findings suggest that SESN2 appears to be essential for inhibiting NLRP3 inflammasome hyperactivation, reducing CASP-1-dependent pyroptosis, and improving sepsis outcomes through stabilization of the ER. The present study might have important implications for exploration of novel potential therapeutic targets for the treatment of sepsis complications.
