Inflammasome activation in trauma-hemorrhagic shock

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PROJECT SUMMARY/ABSTRACT Controlling inflammation and cellular damage is the key to preventing and treating multiple organ failure (MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in specific organs remain unknown. This means that despite advances in supportive measures for patients with MOF, there have been few advances in MOF treatments, or in our ability to adequately prevent the onset of MOF. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating the inflammatory response and its effects on cellular death and survival pathways following trauma and hemorrhagic shock with resuscitation (HS/R). In this proposal we will continue to investigate novel molecular pathways following HS/R that lead to activation of caspase-11 in end-organs, particularly liver. We will also determine how activation of inflammatory caspases regulates cell death and inflammation, which in turn determines organ cell survival after HS/R. Knowing how these cell-signaling pathways function and interact may guide us toward future therapeutic targets for prevention and treatment of MOF after trauma. Inflammatory caspases include caspases-1, 11 (mice), 4/5 (human), and are associated with inflammatory cell death (pyroptosis) and release of inflammatory cytokines (IL-1β, IL-18). Caspase-11 was recently identified as the intracellular receptor for lipopolysaccharide (LPS) and forms what has been termed the non-canonical inflammasome. LPS-mediated caspase-11 activation in macrophages results in cleavage of gasdermin D (GsdmD) and subsequent release of IL-1β, induction of pyroptosis, and initiation of NLRP3 inflammasome and caspase-1 activation. Caspase-11 can also be activated by endogenous oxidized phospholipid (oxPAPC) in LPS-primed dendritic cells, although this interaction does not result in pyroptosis. Our exciting new data show that caspase-11 is activated during HS/R, a non-infectious/sterile injury model, suggesting a novel mechanism of activation of caspase-11 by endogenous damage associated molecular patterns (DAMPs) without a requirement for LPS. We show that once again mitochondria are integral in activation of inflammatory responses after HS/R, and cardiolipin externalization on damaged and stressed mitochondria can activate caspase-11. Surprisingly activation of caspase-11 in HC after HS/R does not lead to pyroptosis, but is vital for active release of HC HMGB1 in exosomes, and caspase-11 activation is detrimental in HS/R. Our preliminary findings lead us to our main hypothesis that DAMP-induced caspase-11 activation has cell specific functions during HS/R, and is an important regulator of cell death and organ damage. We expect to confirm novel, mitochondrial DAMP-mediated pathways of activation of caspase-11, and novel functions of caspase-11 in liver that may make it an attractive therapeutic target during trauma/HS.