Sublytic pyroptosis blocks Schwann cell remyelination through caspase-1-mediated Tyro3 cleavage

Inflammasomes canonically trigger pyroptotic cell death through GSDMD-mediated membrane rupture. This study investigates a distinct sublytic pyroptosis in Schwann cells following peripheral nerve injury, where inflammasome activation causes functional impairment without extensive cell death. Using a mouse sciatic nerve transection-repair model combined with in vitro and in vivo analyses, we examined NLRP3 inflammasome activation and cell fate. Primary Schwann cell cultures and RSC96 cells were used for biochemical assays, while ultrastructural analyses were performed on sciatic nerve segments. Despite NLRP3 inflammasome activation, Schwann cells showed minimal GSDMD cleavage and maintained membrane integrity, resulting in low cell death rates (~ 8% in primary mouse Schwann cells and ~ 2–3% in RSC96 rat Schwann cells). However, these surviving cells failed to transition from repair to myelinating phenotype. Activated Caspase-1 directly cleaves Tyro3 receptor at Asp495, detaching the intracellular kinase domain and abolishing receptor function. This proteolytic inactivation disrupts the Gas6-Tyro3-Fyn signaling axis essential for Schwann cell myelination. Combined treatment with Caspase-1 inhibitor VX-765 and Gas6 prevented Tyro3 cleavage, restored downstream signaling, and promoted expression of myelin transcription factors Oct6 and Krox20 as well as myelin basic protein (MBP). In vivo application significantly enhanced myelin thickness, axon regeneration, and functional recovery assessed by sciatic function index and electrophysiology. Sublytic pyroptosis represents a novel inflammasome-mediated proteolytic receptor inactivation as a previously unrecognized mechanism, distinct from classical pyroptosis. Targeting this pathway with VX-765 and Gas6 represents a promising therapeutic strategy for peripheral nerve regeneration.