University of Ottawa

Purpose

The objective of this collaboration is to test how systemic disruption of sphingolipid and phospholipid metabolism converges on systemic and nervous system-based immune responses to activate the NLRP3 inflammasome. We propose that this activation leads not only to cytokine production but, ultimately, ensures a vicious cycle of systemic aberrant immune responses by perpetuating pathological release of neurotoxic lipid mediators. Here we, will identify, using in vitro models and unbiased lipidomic approaches, the lipid mediators that initiate NRLP3 inflammasome activation, establish whether this induction is required to sustain systemic lipid dysregulation, and finally provide proof-of-principle that inhibiting the NLRP3 inflammasome will reverse the induction by pro-inflammatory lipid mediators.