PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury

Abstract

AbstractCell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offers a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10As role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1{beta}, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1{beta}, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10s established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising.