Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells

Abstract

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.

Dynamic Monitoring of Immunoinflammatory Response Identifies Immunoswitching Characteristics of Severe Acute Pancreatitis in Rats

“…It was hypothesized that the increase in the number of intestinal macrophages and dendritic cells at 1–3 h could be related to the activation of pancreatic enzymes in pancreatic cells, which led to a large number of immune cells activated and chemoattracted to the intestine, further activating the intestinal innate immune cells, and ultimately resulting in an enhanced inflammatory response. However, the number of intestinal macrophages and dendritic cells was decreased at 6–72 h, when the intestinal innate cells could trigger pyroptosis, causing a more intense inflammatory cascade with massive death of immune cells ( 57 ). After 120 h, the number of intestinal macrophages and dendritic cells gradually returned to normal levels, and the SAP rats were in a self-healing state.…”

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

“…Many studies have confirmed the pyroptosis of peripheral immune cells in patients in septic shock ( 91 , 92 ). Recently, we observed pyroptosis of splenic dendritic cells (DCs) in CLP-induced septic mice ( 93 ). Similarly, Xu et al noticed the pyroptosis of neural cells in septic mice and found that the inhibition of pyroptosis could alleviate brain damage and cognitive impairment in SAE.…”

Mitochondrial DNA mediates immunoparalysis of dendritic cells in sepsis via STING signalling

“…Previous studies have indicated that depletion of DCs seriously affects the prognosis of sepsis, which was regarded as a vital target for sepsis treatment. 5,6 Sepsis associated hyperinflammation allows accumulation of damage-associated molecular patterns (DAMPs) in peripheral circulation, including high mobility group protein-1 (HMGB1), 7 histones, mitochondrial DNA (mtDNA), and so forth. 8 DAMPs serve as potent activators of the immune system in initiating and perpetuating non-infectious inflammation to induce systemic inflammation, leading to organ injury and paralysis of immune cells, 9,10 thus resulting in poor prognosis of sepsis.…”

“…As the most important antigen presenting cell, DCs play an essential role in bridging innate and adaptive immunity, participating in maintaining immune homeostasis. Previous studies have indicated that depletion of DCs seriously affects the prognosis of sepsis, which was regarded as a vital target for sepsis treatment 5,6 . Sepsis associated hyperinflammation allows accumulation of damage‐associated molecular patterns (DAMPs) in peripheral circulation, including high mobility group protein‐1 (HMGB1), 7 histones, mitochondrial DNA (mtDNA), and so forth 8 .…”