STING-mediated intestinal barrier dysfunction contributes to lethal sepsis

Author(s):
Qiong-yuan Hu; Robert Sawyer; Xiuwen Wu; Jianan Ren

Background:

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

Hypothesis:

We therefore investigated the role of STING signaling in sepsis and intestinal barrier using patients samples and mouse model of sepsis. We hypothesis that STING is involved in the pathogenesis of sepsis by mediating IEC apoptosis induced by increased intestinal inflammation.

Methods:

Animals and severe CLP model; Measurement of intestinal permeability and bacterial translocation; Histology and Immunofluorescence; Quantitative PCR analysis; Western blot analysis; Cell culture preparation ;Serum and tissue cytokines levels;Analysis of apoptosis by TUNEL analysis.

Results:

In abdominal sepsis patients, STING expression was elevated in peripheral blood mononuclear cells and intestinal specimens compared with healthy controls, and the degree of STING expression in human lamina propria correlated with intestinal inflammation in sepsis patients. Moreover, elevated STING expression was associated with high level of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecum ligation perforation (CLP). STING knockout mice showed alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice administrated with STING agonist (DMXAA) developed more severe IEC apoptosis and systemic inflammatory response. We also showed that the blocking of TNF or type I interferon signaling suppressed DMXAA-induced systemic shock and IEC apoptosis. In addition, we demonstrated that mitochondrial DNA was released during sepsis, which induced intestinal inflammatory response through activating the STING pathway.

Conclusions:

Our results indicate that STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and disrupting intestinal barrier. Our findings suggest that STING regulation may be a promising strategy to promote mucosal healing and protect intestinal barrier in sepsis patients.