11β-HSD1 may Aggravate Sepsis-associated Endothelial Dysfunction by Activating the NF-κB/MAPK Pathway and NLRP3 Inflammasome.

Background

Endothelial dysfunction is a major contributor to sepsis-related organ dysfunction, but the underlying molecular mechanism of endothelial damage remains poorly understood.

Objective

This study aimed to investigate whether 11β-HSD1 promotes sepsis-induced endothelial dysfunction by activating the NF-κB/MAPK pathway and NLRP3 inflammasome.

Methods

Lipopolysaccharide (LPS)-stimulated human microvascular endothelial cells (HMEC-1) and a cecal ligation and puncture (CLP)-induced mouse model were used as in vitro and in vivo models of sepsis, respectively. The involvement of specific pathways was examined using the 11β-HSD1 inhibitor BVT.2733, along with NLRP3 knockdown and knockout models. Inflammatory cytokines were quantified by ELISA, while endothelial injury- and inflammasome-related molecules were assessed by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, serum cortisol (COR) and NLRP3 levels were measured in patients with sepsis.

Results

In LPS-treated HMEC-1 cells and aortic tissues from CLP-induced septic mice, 11β-HSD1 expression was significantly upregulated, accompanied by decreased levels of eNOS and VE-cadherin, increased release of inflammatory cytokines, and activation of NF-κB/MAPK signaling and the NLRP3 inflammasome. Treatment with BVT.2733 or NLRP3 blockade partially reversed these changes and attenuated endothelial damage. Clinically, serum cortisol (COR) and NLRP3 levels were elevated in septic patients, and this elevation was more pronounced in non-survivors.

Conclusion

11β-HSD1 may exacerbate sepsis-associated endothelial dysfunction by promoting NF-κB/MAPK signaling and NLRP3 inflammasome activation. Targeting this axis represents a potential therapeutic approach for sepsis-related endothelial injury, though further validation is warranted.