β-arrestin-1 negatively regulates inflammatory response to polymicrobial sepsis in mice (110.11)

Abstract

Abstract β-arrestins are scaffolding proteins that regulate a number of receptor signaling pathways including Toll-like receptors. We recently demonstrated that mice lacking either β-arrestin-1 or β-arrestin-2 are protected from lipopolysaccharide-induced lethality and have a markedly reduced inflammatory response. To assess the role of β-arrestin-1 in a clinically relevant model of sepsis, we subjected wild type and β-arrestin-1 knockout mice to cecal-ligation and puncture (CLP) to mimick septic peritonitis and polymicrobial sepsis. Surprisingly, we found that, mortality of β-arrestin-1 knockout mice was significantly enhanced compared to the wild type mice after CLP. Consistent with lethality, β-arrestin-1 knockout mice had markedly elevated inflammatory cytokine levels in the plasma, peritoneal cavity, and bronchoalveolar fluid. Enhanced systemic inflammatory response of β-arrestin-1 knockout mice was associated with significantly enhanced infiltration of immune cells into the peritoneal cavity after induction of septic peritonitis. Together, these results demonstrate that, contrary to its role in lipolysaccharide-TLR4 signaling in vivo, β-arrestin-1 is a negative regulator of inflammation induced by polymicrobial sepsis and that the phenotype of the mice may be related to a potentially aberrant immune response from excess infiltration of immune cells. These results also suggest that the role of β-arrestin-1 in this model is likely independent of its role in TLR4 signaling in vivo.