Red blood cells undergo lytic programmed cell death involving NLRP3 by Yaozhen Chen & Shouwen Chen & Zhixin Liu & Yafen Wang & Ning An & Yutong Chen & Yihao Peng & Zheng Liu & Qin Liu & Xingbin Hu instant download

Red blood cells undergo lytic programmed cell death involving NLRP3 by Yaozhen Chen & Shouwen Chen & Zhixin Liu & Yafen Wang & Ning An & Yutong Chen & Yihao Peng & Zheng Liu & Qin Liu & Xingbin Hu instant download

SUMMARYThe canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis.However, inhibition strategies targeting complement are not always as efficient as expected, indicatingthat unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events inmature RBCs following complement activation. The collected evidence demonstrates that complementinduced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associatedspeck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces theproteolysis of b-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we referto as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmalnocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.