Project leader: Tony Bruns / Sachin Deshmuk
Doctoral candidate: Michael Rooney
Background and previous work
Cellular stress responses dose-dependently activate the autophagy pathway in order to protect the cell against various injuries. In the clinical course of sepsis, autophagy is induced within the liver only transiently and its abrogation correlates with the occurrence of septic liver injury. Inducing and/or enhancing autophagy by anthracyclin-mediated genotoxic stress prevents cell death, inflammatory responses, and organ injury in mouse models of abdominal sepsis. As key regulators of innate immune responses, the inflammasomes control the release of pro-inflammatory cytokines and alarmins, which has proven protective in some settings of infectious diseases because of recruiting immune cells to the site of infection. However, its excess activation needs to be restricted in order to avoid organ damage and improve survival. The induction of autophagy in monocytes is one critical control mechanism to limit inflammasome activation underlining the tight interplay of autophagy and the inflammasome.
Specific aims and working programme
This project aims at investigating the interplay of hepatic autophagy and inflammasome activation in a mouse model of abdominal sepsis in order to identify protective mechanisms of how low-dose stress responses contribute to tissue tolerance and organ protection. We hypothesise that the induction of autophagy by genotoxic stress limits hepatic NLRP3 and AIM2 inflammasome activation through phagosomal engulfment of inflammasome components thereby mitigating septic liver injury in a model of peritoneal contamination and infection (PCI). We will assess the dose-dependent efficacy of epirubicine prophylaxis on preventing liver damage and assess the liver for DNA damage responses, evidence for autophagy and its co-localization with NLRP3 and AIM2 inflammasome components. To investigate whether stress-induced resistance to organ damage is mediated via engulfment of the NLRP3 inflammasome, we will also study the effects in NLRP3-/- knockout mice treated with PBS or epirubicine prior to the induction of sepsis.