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EBioMedicine. 2019 Mar;41:497-508. doi: 10.1016/j.ebiom.2019.02.055. Epub 2019 Mar 14.

STING-mediated intestinal barrier dysfunction contributes to lethal sepsis.

Author information

1
Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Medical School of Nanjing University, Nanjing, China.
2
Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
3
Department of colorectal and anal surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
4
Medical School of Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Collaborative Innovation Center of Genetics and Development, Model Animal Research Center, Nanjing, China.
5
Medical School of Nanjing University, Nanjing, China.
6
Medical School of Nanjing University, Nanjing, China; Department of Surgery, Salford Royal NHS Foundation Trust, Stott Lane, Salford, United Kingdom. Electronic address: dom.slade@talktalk.net.
7
Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address: lygwxw@163.com.
8
Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address: JiananR@gmail.com.

Abstract

BACKGROUND:

Gut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.

METHODS:

We investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.

FINDINGS:

In human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.

INTERPRETATION:

Our results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.

KEYWORDS:

IEC apoptosis; Intestinal inflammation; STING; Sepsis

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