Sestrin2 (SESN2) is a highly evolutionary conserved protein and involved in different cellular responses to various stresses. However, the potential function of SESN2 in immune system remains unclear. The present study was designed to test whether dendritic cells (DCs) could express SESN2, and investigate the underlying molecular mechanism as well as its potential significance. Herein, we firstly reported that SESN2 was expressed in DCs after high mobility group box-1 protein (HMGB1) stimulation and the apoptosis of DCs was obviously increased when SESN2 gene silenced by siRNA. Cells undergone SESN2-knockdown promoted endoplasmic reticulum (ER) stress (ERS)-related cell death, markedly exacerbated ER disruption as well as the formation of dilated and aggregated structures, and they significantly aggravated the extent of ERS response. Conversely, overexpressing SESN2 DCs markedly decreased apoptotic rates and attenuated HMGB1-induced ER morphology fragment together with inhibition of ERS-related protein translation. Furthermore, sesn2 −/− -deficient mice manifested increased DC apoptosis and aggravated ERS extent in septic model. These results indicate that SESN2 appears to be a potential regulator to inhibit apoptotic ERS signaling that exerts a protective effect on apoptosis of DCs in the setting of septic challenge.

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.

Background: To explore the epidemiology, clinical features, risk indicators, and long-term outcomes of neurological complications caused by veno-arterial extracorporeal membrane oxygenation (V-A ECMO).Methods: We retrospectively analyzed 60 adult patients who underwent V-A ECMO support in our unit from February 2012 to August 2020. These patients were separated into the neurological complications group (NC group) and the non-neurological complications group (nNC group). The differences in basic data and ECMO data between the two groups were compared. The data of long-term neurological prognosis were collected by telephone follow-up.Results: Thirty-nine patients (65.0%) had neurological complications. There were significant differences between the two groups in terms of median age, hypertension, median blood urea nitrogen, median troponin I (TNI), median lactic acid, pre-ECMO percutaneous coronary intervention, continuous renal replacement therapy (CRRT), median Sequential Organ Failure Assessment score, median Acute Physiology and Chronic Health Evaluation II score, median peak inspiratory pressure, median positive end expiratory pressure, and median fresh frozen plasma (P < 0.05). The median Intensive Care Unit length of stay (ICU LOS), 28-day mortality, median post-ECMO vasoactive inotropic score, non-pulsate perfusion (NP), and median ECMO duration of the NC group were significantly higher than those of the nNC group (P < 0.05). Furthermore, multiple logistic regression analysis revealed that TNI (P = 0.043), CRRT (P = 0.047), and continuous NP > 12 h (P = 0.043) were independent risk indicators for neurological complications in patients undergoing ECMO. Forty-four patients (73.3%) survived after discharge, and 38 patients (63.3%) had Cerebral Performance Category score of 1–2. And there were significant differences between the two groups in long-term neurological outcomes after discharge for 6 months (P < 0.05).Conclusion: The incidence of neurological complications was higher in patients undergoing V-A ECMO and was closely related to adverse outcomes (including ICU LOS and 28-day mortality). TNI, CRRT, and continuous NP > 12 h were independent risk indicators for predicting neurological complications in ECMO supporting patients. And the neurological complications of patients during ECMO support had significant adverse effect on long-term surviving and neurological outcomes of patients after discharge for 6 months.

Although the Pink1/Parkin-mediated mitophagy is closely related to in ammation and immunoregulation, its effect on apoptosis of splenic dendritic cells (DCs) in sepsis remains unknown. Here, our current study demonstrates that mitophagy is enhanced, and apoptosis of DCs is increased during sepsis in Wild Type (WT) mice. It also shows that mitophagy occurs in the process of the sepsis-induced apoptosis of DCs.Moreover, the level of mitophagy of Pink1-knockout (Pink1-KO) mice is lower than that of WT mice, while the apoptosis of DCs of Pink1-KO mice is increased further more than that of WT mice during sepsis. The mitochondrial dysfunction in DCs is aggravated in Pink1-KO mice during sepsis, which suggests that Pink1/Parkin-mediated mitophagy regulates the apoptosis of DCs by improving mitochondrial function.Thus, an impaired Pink1/Parkin-mediated mitophagy exacerbates the apoptosis of DCs and it might represent a novel therapeutic target to prevent sepsis in the future.