Noncanonical NLRP3 Inflammasome Activation Elicits the Programmed Death of Red Blood Cells

The canonical complement-mediated lysis of red blood cells (RBCs) leads to serious pathogenesis. However, inhibition strategies targeting complements are not always as efficient as expected in the clinical setting. To seek for more efficient therapy, we investigated the intracellular events in RBCs following complement activation, which had been neglected for a long time. Here, we demonstrated that complement-induced hemolysis was a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs were identified to engage in the assembly of the NLRP3-caspase-8 inflammasome. Activated caspase-8 directly induced β-spectrin proteolysis, thereby disrupting the RBC membrane skeletal network, named as spectosis. Our study also demonstrated that spectosis signaling was activated in patients with hemolytic anemia, and blocking spectosis could substantially attenuate complement-induced hemolysis. These findings unveil a programmed death cascade in mature RBCs, which may have implications for the treatment of hemolytic disorders.