Caspase-11 regulates HMGB1 release from liver during polymicrobial sepsis (INM2P.348)

Abstract

Abstract Caspase-11 was recently identified as the cytosolic LPS receptor, although little is known about its role in a polymicrobial sepsis. We subjected WT and caspase-11-/-(casp-11-/-) mice to polymicrobial sepsis in the form of cecal ligation and puncture(CLP). By 18h caspase-11 was upregulated and activated in multiple tissues, including liver. Casp-11-/- mice had significantly lower bacterial levels in peritoneum (3.9E+5±2.4E+5vs 8.3E+6±4.8E+6CFU/mL;p<0.05), lower systemic cytokine levels (IL1b;IL6) and reduced peritoneal neutrophil death (3.1±0.3vs6.7±0.5%;p<0.05) vs WT. HMGB1 has been associated with late mortality during sepsis and hepatocytes (HC) are major producers of HMGB1 after CLP, as shown by significantly decreased plasma HMGB1 in HC-specific HMGB1-/- mice at 18h after CLP vs WT(11±3vs53±9ng/mL;p<0.05). Similarly, plasma HMGB1 levels in casp-11-/- mice were significantly lower after CLP vs WT(14±2vs39±8ng/mL;p<0.05). To confirm a role for caspase-11 in HMGB1 release, we stimulated primary isolated HC with LPS(100ng/mL) for 24h in vitro. Media HMGB1 level increased significantly in WT HC after LPS stimulation, but not in casp-11-/- HC. Furthermore, HC cell death was not different between WT and casp-11-/- HC +/- LPS suggesting the release of HC-HMGB1 regulated by caspase-11 is not passive via induction cell death. Our data suggest novel roles for caspase-11 in regulation of immune responses during sepsis including the regulation of HMGB1 release by epithelial cells.