Enzymatically inactive caspase-1 mediates a proinflammatory phenotype in mice

Introduction The proinflammatory enzyme caspase-1 belongs to the family of cystein proteases and plays a pivotal role in innate immunity. Classically, caspase-1 mediated proinflammatory signaling is thought to be dependent on its enzymatic activity. Interestingly, a number of patients carrying variants of the CASP1 gene show proinflammatory symptoms like febrile episodes despite of reduced enzymatic activity of the caspase-1 protein resulting in decreased IL-1b production. In vitro investigations of this contradictory phenomenon revealed receptor interacting protein kinase 2 (RIP2) as a potential mediator between decreased caspase-1 activity and increased inflammation. In order to investigate the role of enzymatically inactive caspase-1 in an in vivo situation, we generated a mouse model expressing enzymatically inactive caspase-1.