Type‐I interferon‐mediated Akt/mTORC2 signaling regulates autophagy and inflammasome activation in mouse liver injury/sepsis model

Abstract

Background: Sepsis is a clinical syndrome due to dysregulated systemic immune response to infection and tissue injury that causes life‐threatening multiple organ failure. In murine model of sepsis and hepatic inflammatory injury induced by infection with Ehrlichia, an obligate intracellular bacteria targeting liver that compromises the immune system, we have shown that type I interferon (IFN‐I) signaling triggered liver injury, excessive inflammation, and impaired bacterial clearance. We and others have also showed that Ehrlichia exploits autophagy proteins for their own survival and replication. This study was designed to investigate the role of IFN‐I signaling in the regulation of autophagy and inflammatory responses in immune and non‐immune cells such as macrophages and hepatocytes, respectively, during sepsis.Results: In this study, we found that IFN‐I signaling promotes autophagy and activates non‐canonical inflammasome pathway mediated by caspase 11 in primary murine macrophages and hepatocytes. Enhancement of autophagy in hepatocytes and macrophages via IFN‐I stimulation or rapamycin treatment increased bacterial replication. Conversely, inhibition of autophagy in macrophages using type III Phosphatidylinositol 3‐kinases (PI‐3K) inhibitor (3‐MA) or blocking IFN‐I receptor (IFNAR) signaling attenuated autophagy, abrogated caspase 11 activation, and decreased intracellular bacteria. These data suggest that IFN‐I signaling impair anti‐bacterial immunity via induction of autophagy. Further, IFN‐I signaling also induced secretion of several chemokines and growth factors (e.g. MIP1alpha, MCP‐1, RANTES, KC, GM‐CSF and VEGF) by hepatocytes that are known to promote excessive infiltration of immune and inflammatory cells into the liver. Finally, microarray analysis identified mTORC2, rapamycin‐insensitive companion of mTOR, and WNT, elevated in sepsis, signaling components to be enhanced in IFN‐I stimulated and infected hepatocytes, which may play a role in IFN‐mediated enhancement of autophagy and inflammation.Conclusions: Together, our novel findings identify the IFN‐1‐mediated Akt/autophagy axis as a key regulator of innate inflammatory response in the mouse liver cells. By identifying molecular mechanisms of IFN‐1‐mediated Akt/autophagy/mTORC2 signaling during sepsis, our study provides a rationale for therapeutic approaches to manage inflammation and liver injury during sepsis.Support or Funding InformationThis work was supported by grants from NIAMS, NIGMD, and NIAID (AR68317 CCY, GM102146 MS, and R56A1097679 NI)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.