Burgener, S.; Milner, M. T.; Dey, S.; Morgan, P.; Blackmore, D. G.; Frampton, E.; Miller, G.; Durate de Oliveira, M.; Kenney, K. M.; Bajracharya, R.; Baumgartner, U.; Collins, T. T. J. C.; Xiong, Z.; Nguyen, Q.; Meikle, P.; Bodea, L.-G.; Clouston, A.; Boucher, D.; Goetz, J.; Murphy, A. J.; Kaye, P. J.; Schroder, K.

Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by the caspase-1 (CASP1) protease, to allow inflammation to resolve and reinstate tissue homeostasis. It is unknown how CASP1 terminates its activity in vivo. Here, we use a knock-in mouse model in which the CASP1 CARD domain linker (CDL) is mutated to prevent self-cleavage (Casp1.CDL mice) to show that CASP1 CDL autoproteolysis terminates CASP1 activity in vivo. We examined these mice under homeostatic conditions and in response to major physiological challenges. In the brain, CASP1 CDL mutation caused anxiety-like behaviour under homeostatic conditions, and exacerbated hippocampal spatial learning deficits in the APP23 genetic model of amyloid-induced neurodegeneration. In the bone marrow, CASP1 CDL mutation promoted steady-state granulopoiesis. In a model of diet-induced liver disease, CASP1 CDL mutation accelerated liver steatosis and promoted liver immune cell infiltration, inflammation and damage. In a liver healing model, CASP1 CDL mutation delayed disease resolution, indicating that CASP1 autocleavage is required to restore homeostasis after a major challenge to organ function. Our data reveal that CASP1 CDL self-cleavage terminates CASP1 inflammatory programs in vivo to maintain homeostasis in steady-state, restore homeostasis after a major challenge to organ function, and suppress inflammasome-driven diseases. These data identify CASP1 as a prime anti-inflammatory drug target, as CASP1 inhibitors may enforce homeostasis and prevent inflammasome-driven diseases.