The NLRP1 inflammasome is an essential and selective mediator of axon pruning in neurons.

Axon pruning is a unique process neurons utilize to selectively degenerate axon branches while keeping the neuronal cell body intact. The mechanisms of axon pruning have much in common with those of apoptosis. Both axon pruning and apoptosis pathways require key apoptotic proteins (Bax, Caspase-9, Caspase-3). Interestingly, axon pruning does not require Apaf-1, a key member of the apoptosome complex. As such, exactly how caspases are activated in an apoptosome-independent manner during axon pruning is unknown. Here we show that neurons utilize the NLRP1 inflammasome, an innate immune sensor of pathogens, specifically for axon pruning. Strikingly, NLRP1b-deficient neurons were unable to prune axons both in vitro and in vivo, but fully capable of degenerating during apoptosis. Our results reveal NLRP1 as an immune molecule engaged by neurons for an unexpected physiological function independent of its pathogen-induced proinflammatory role.