190: Investigating how the immunosuppressant cyclosporin A inhibits NLRP3 inflammasome activation

Caspase-1 associated with the NLRP3 inflammasome cleaves and thereby activates the pro-inflammatory cytokines IL-1b and IL-18 [1] . NLRP3-caspase-1 promotes immune responses to microbial infection, but is also pathologically activated in diseases such as gout, diabetes and cryopyrin-associated autoinflammatory syndromes [2] . The mechanisms of NLRP3 activation remain controversial, but recent studies have suggested that defects in mitochondrial homeostasis are responsible for NLRP3 activation [3] , [4] . Cyclosporin A inhibits NLRP3 activation [5] , [6] . It has been proposed that because cyclosporin A targets cyclophilin D to prevent mitochondrial permeability transition pore (MPT) opening, that MPT is required for NLRP3 functioning. We observed, however, that deletion of cyclophilin D did not prevent NLRP3 activation, and that cyclosporin A still inhibited NLRP3 in cyclophilin D deficient macrophages. Here we investigate other cyclosporin A targets to identify how cyclosporin A potently shuts down NLRP3 activity, and uncover novel proteins essential of NLRP3-driven immune responses.