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.