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

Li-Xue Wang,Ren-Qi Yao,Chao Ren,Yi-Nan Luo,Yong-Ming Yao,Xiao-Mei Zhu,Yue Yin,Ning Dong,Yao Wu

doi:10.1007/s00018-021-03970-z

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.

Highlights

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and remains one of the predominant medical challenges in intensive care units [1, 2]
We examined the dendritic cells (DCs) pyroptosis rate and found that it was significantly increased at 6 h post cecal ligation and puncture (CLP), and peaked at 24 h (Fig. 1A)
These results suggested that consistent with DC pyroptosis, the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome was activated after sepsis

Summary

Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and remains one of the predominant medical challenges in intensive care units [1, 2]. The degree to which the number of splenic leukocytes, including macrophages, dendritic cells (DCs), and T lymphocytes, is reduced is a critical determinant of the severity of sepsis and the prognosis of patients with sepsis and septic shock [3, 4]. DCs are the most important professional antigen-presenting cells and play pivotal roles in initiating adaptive immune responses [5, 6]. It has been documented that depletion of DCs occurs in the early stages of sepsis and that the extent of depletion is strongly associated with fatal outcomes among septic patients [7, 8]. The precise mechanisms underlying the depletion of DCs during sepsis remain unclear. Pyroptosis is a subtype of programmed necrotic cell death that induces inflammation by promoting the activation of at least one type of cytosolic inflammasome [9]

Methods

Results

Conclusion