Targeting Inflammasomes to Treat Neurological Diseases

Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177-188.