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Project Summary

The NLRP3 inflammasome a protein complex in myeloid cells whose activation leads to the secretion of interleukin-1 family cytokines. Signals of danger and tissues stress lead to NLRP3 activation, and NLRP3 is a major instigator of disease-associated inflammation and immune pathology in many tissue including the CNS, where it has been implicated in Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS). Mutations in NLRP3 cause a group of auto-inflammatory diseases termed cryopyrin-associated periodic syndromes (CAPS), some of which display CNS involvement. However, little is known about a potential role of NLRP3 in maintaining homeostasis in the CNS. Here we aim to characterise NLRP3 activation in the CNS, and understand how excessive activation of NLRP3 leads to pathological inflammation in the CNS. To this end, we propose to 1) establish an ex vivo culture system that will allow characterization of NLRP3 activation and its consequences in a complex CNS tissue; 2) determine the role of NLRP3 in models of resolving neurological injury, where we hypothesize that transient NLRP3 activation has a role in returning the tissue to homeostasis, and 3) understand how activation of NLRP3 in otherwise healthy CNS tissue leads to CNS inflammation in the mouse model of CAPS. Overall, these studies will shed light on the early events of pathogenesis of NLRP3-driven neuroinflammation that might guide therapeutic interventions not only in rare CAPS, but also in more prevalent diseases such as MS and Alzheimer’s disease or Parkinson’s disease.