2. Academic Validation
  3. Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

  • Cell Death Dis. 2021 Jun 11;12(6):606. doi: 10.1038/s41419-021-03896-1.
Shilong Sun  # 1 2,  Zehua Duan  # 1,  Xinyu Wang  # 1,  Chengnan Chu 1,  Chao Yang 1,  Fang Chen 1 3,  Daojuan Wang 4,  Chenyang Wang 2,  Qiurong Li 5,  Weiwei Ding 6 7
Affiliations

Affiliations

  • 1 Division of Trauma and Surgical Intensive Care Unit, Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, P. R. China.
  • 2 Key Laboratory of Intestinal Injury, Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, P. R. China.
  • 3 School of Medicine, Southeast University, Nanjing, 210009, P. R. China.
  • 4 State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, Jiangsu, P. R. China.
  • 5 Key Laboratory of Intestinal Injury, Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, P. R. China. liqiurongjue@126.com.
  • 6 Division of Trauma and Surgical Intensive Care Unit, Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, P. R. China. dingwei_nju@hotmail.com.
  • 7 The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, P. R. China. dingwei_nju@hotmail.com.
  • # Contributed equally.
PMID: 34117211 DOI: 10.1038/s41419-021-03896-1
Abstract

Increased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal Apoptosis and tight junction injury. Finally, TLR9 Antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and Apoptosis. Suppression of the TLR9-ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

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