Neuroinflammation in cryopyrin-associated periodic fever syndrome: Implications of the NLRP3 inflammasome in the central nervous system

• Applicant: Dr. Elisabeth Schuh
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421414975

Despite the important role of IL-1β in host defence against infection, dysregulated NLRP3 inflammasome activation has a causative role in a number of acquired neurological diseases including stroke, multiple sclerosis, meningitis, and Alzheimer’s diseases. However, the relevance of inflammasome signaling to human health was firstly demonstrated in cryopyrin-associated periodic syndromes (CAPS), a monogenetically inherited autoinflammatory condition. Without treatment, one third of CAPS patients develop amyloidosis with consequent renal failure and death. Therapeutic strategies include the blockade of the IL-1β receptor or the depletion of the secreted IL-1β by recombinant proteins. These treatment strategies are therapeutically cumbersome since CNS inflammation is often therapy refractory.Microglia, astrocytes and neurons have all been reported to express the NLRP3 inflammasome, but little is known about how this diversity affects the regulation of IL‑1β signaling at the tissue level. To that date, it is unknown which particular cell type controls neuroinflammation in the autoinflammatory condition CAPS. Therefor the research project proposed herein seeks to identify the cellular source of IL-1β secretion during neuroinflammation in CAPS by investigating conditional NLRP3 mouse models harboring knock-in mutations in microglia, CNS invading monocytes or neutrophils via state-of-the art molecular and imaging techniques. Animal data will be complemented by phenotyping human CSF and sera samples of CAPS mutation carriers.A more comprehensive understanding of the NLRP3 inflammasome in the CNS, studied both in mouse and men as proposed, will unveil the development of novel therapies that target its activation and provide the base of a precision medicine model.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Dr. Seth Masters