Abstract
Gain-of-function mutations in the Nlrp3 inflammasome cause auto-inflammatory diseases termed cryopyrin-associated periodic syndromes (CAPS). Expressing a CAPS-associated Nlrp3 mutant selectively in either macrophages or neutrophils results in severe inflammation in mice. While it is known that Nlrp3 activation results in lytic cell death due to facilitating Gasdermin D (GSDMD) to form pores in the cell membrane, we will investigate the cell type specific mechanisms by which GSDMD-mediated cell death in either macrophages of neutrophils contributes to Nlrp3-induced CAPS in mice. Using CAPS mice expressing Nlrp3 selectively in either macrophages or neutrophils, we will investigate how different cell death modes control Nlrp3-induced release of pro-inflammatory factors in these mice. In addition, we will analyze serum inflammatory profiles resulting from GSDMD-dependent cell death in either macrophages or neutrophils, and we will aim to identify novel inflammatory mediators produced upon Nlrp3 mutant expression in these cell types. Finally, using a genetic proof-of-principle approach in CAPS mice, we will evaluate the efficacy and safety of GSDMD targeting as a potential future treatment for CAPS patients. A better understanding of the cell type specific mechanisms by which GSDMD-mediated cell death drives Nlrp3-induced CAPS will increase our understanding of how Nlrp3-induced cell death regulates several other inflammatory diseases.
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