Modulating inflammasome activity and inflammation in the central nervous system

Abstract

Compositions and methods for reducing inflammation in the central nervous system (CNS) of a mammal that has been subjected to a stroke, traumatic injury to the CNS such as traumatic brain injury (TBI), spinal cord injury (SCI), or having an autoimmune or CNS disease have been developed. The compositions and methods described herein include antibodies that specifically bind to at least one component (e.g., ASC, NALP1) in a mammalian inflammasome (e.g., the NALP1 inflammasome) and have use as treatments for SCI, TBI, stroke, and autoimmune and CNS diseases in a mammal. In a rodent model of SCI, therapeutic neutralization of ASC using a polyclonal antibody that specifically binds to ASC inhibited the inflammasome, reduced caspase-1 activation, XIAP cleavage, and interleukin processing, resulting in significant tissue sparing and functional improvement. Additionally, in a rodent model of TBI, neutralization of ASC after TBI reduced caspase-1 activation and XIAP cleavage. Further, in a rodent thromboembolic stroke model, neutralization of NLRP1 resulted in reduced histopathological damage in mice and reduced cytokine activation, suggesting that the inflammasome complex forms in the brain after stroke and is a therapeutic target for reducing the detrimental consequences of post-stroke inflammation.