Friday, August 5, 2022

The NLRP3 inflammasome has been identified as a key immune sensor for tissue damage. Although NLRP3 inflammasome assembly/activation leads to the production of inflammatory messengers (called cytokines) that alert the host immune system to initiate inflammatory responses, its dysregulation often results in overt diseases due to uncontrolled inflammation. Unfortunately, exposure to a number of environmental toxicants including PFAS have been shown to induce NLRP3 inflammasome activation that in turn initiates an undesirable inflammatory response, thereby causing numerous pathologies. Although stimulating agents have not been demonstrated to directly bind NLRP3, they are able to trigger mitochondrial damage and subsequent release of mitochondrial contents that somehow signal the activation of NLRP3 inflammasome. We seek to identify the mitochondrial ligand responsible for direct NLRP3 activation and probe the molecular determinants of recognition for this interaction.