Sestrin2 alleviates sepsis-induced immunosuppression of dendritic cells by regulating mitochondrial dynamics

Mitochondrial dynamics and mitophagy are key mechanisms maintaining mitochondrial quality and homeostasis in inflammatory diseases, though their activation pathways in inflammatory regulation remain unclear. Sestrin2 (Sesn2), a stress-responsive protein critical for cellular homeostasis, was investigated in this study for its regulatory role in mitochondrial dynamics during sepsis and its potential mechanism in dendritic cell (DC) necroptosis.

This study evaluated Sesn2-regulated mitochondrial dynamics proteins such as dynamin-related protein 1 (DRP1), mitochondrial fission factor (MFF), and mitofusin 2 (MFN2) in DCs during sepsis using Western blotting, laser confocal microscopy, and transmission electron microscopy. Lentiviral-transfected cell lines and Sesn2-knockout mouse models were developed to assess Sesn2 deletion's role in DC necroptosis and its impact on immune response signaling pathways post-septic challenge.

Both cecal ligation and perforation (CLP)-induced sepsis and lipopolysaccharide (LPS) stimulation elicited significant alterations in mitochondrial dynamics, and Sesn2 expression peaked at 24 h. When Sesn2 was knocked down, necroptosis and mitochondrial fission of DCs were noticeably increased, while mitochondrial fusion was decreased. Conversely, the overexpression of Sesn2 exerted a significant protective impact on DCs. Consistently, the necroptosis and immunosuppression of DCs and 7-days mortality rate in Sesn2 gene-deficient mice were significantly increased compared with those in wild-type (WT) mice. Furthermore, Sesn2-mediated mitochondrial fusion and division on DCs was identified to be closely associated with the necroptosis pathway, and DRP1-ROS-ZBP1 signaling was obviously involved in down-regulating necroptosis of DCs in the setting of sepsis.

Sesn2-mediated mitochondrial fusion and division can be significantly activated to alleviate the necroptosis of DCs via the DRP1-ROS-ZBP1 pathway in the context of sepsis. Thus, it is of importance that Sesn2 stabilized mitochondrial dynamics might be beneficial for reversing immunosuppression associated with septic complications.