Regional
Programmed cell death resulted from ABO blood group reaction in RBCs
Red blood cells (RBCs) lysis due to biological or mechanical damage can lead to significant morbidity and mortality. However, the intracellular molecular mechanisms underlying RBC lysis remain fully understood, which limits therapeutic and preventive options for hemolytic diseases. In a recent issue of Cell, Chen et al. identify a critical role for the NLRP3-ASC-caspase-8 complex in driving programmed lytic cell death in RBCs.
Human mature RBCs are instrumental in oxygen transport, which is vital for maintaining physiological activity. Damage to RBCs can result in the release of free hemoglobin, which subsequently produces heme that can injure the kidneys, liver, and brain. Consequently, multi-organ dysfunction, cytokine storms, and mortality may occur in affected individuals.
The human ABO blood group system was characterized over 100 years ago, alongside the observation of the complement cascade. One cause of RBC lysis is the activation of complement system, which involves blood group antibodies binding to RBC antigens, leading to the generation of cleavage products to form the membrane attack complex (MAC). Additionally, autoimmune hemolytic anemias (AIHA), paroxysmal nocturnal hemoglobinuria (PNH), and hemolytic transfusion reactions (HTR) are also complement-mediated hemolytic diseases. However, therapies targeting complement components do not always yield satisfactory results in these disorders, suggesting that unknown mechanisms await elucidation.
Recently, Chen et al. observed that RBCs exhibit sequential morphological changes once complement system activated, suggesting the occurrence of programmed cell death. While the assembly of NOD-like receptor (NLR) family member-mediated complexes had not previously been reported in mature RBCs, Chen et al. demonstrated that NLRP3 is essential for the programmed death of RBCs following the complement cascade. The authors provided evidence that caspase-8 cleavage accompanies complement-induced programmed cell death, referred to as spectosis during hemolysis. Subsequently, they gathered robust evidence indicating that potassium efflux activates intracellular NLRP3 in RBCs, which engages apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) for caspase-8 activation. Additionally, β-spectrin forms a cytoskeletal network that stabilizes the lipid membrane and maintains the discocyte morphology of RBCs. Chen et al. demonstrated that the NLRP3-ASC-caspase-8 signaling axis induces a loss of β-spectrin architecture, which regulates spectosis in complement-activated hemolysis.
In terms of clinical application, undoubtedly the therapeutic potential for treating hemolytic disease is a promising proposition based on the findings of Chen et al. The use of various complement inhibitors has transformed the clinical management of hemolytic diseases, including PNH, AIHA, and HTR following blood administration. However, these inhibitors appear to be only partially protective in certain patient subpopulations; thus, additional approaches, such as the development of NLRP3 inhibitors, should be encouraged in the future.
Regarding transfusion medicine, the significance of reports from Chen et al. should be emphasized on different perspectives. First, it is well known that damage-associated molecular patterns (DAMPs), such as ATP, LPS, and nigericin, can activate NLRP3 to trigger inflammation. In this context, ABO blood group reactions, through the complement cascade, also serve as an initiating factor for NLRP3 activation. However, the blood group specificity warrants further investigation. Second, antibodies to blood groups exhibit considerable heterogeneity, with IgG and IgM subsets observed in different reaction environments. In other words, the findings of Chen et al. may be more applicable to intravascular hemolysis.
While extravascular hemolysis also involves the complement cascade, the role of the NLRP3-ASC-caspase-8 signaling axis in this context remains uncertain. Third, the phenomenon of spectosis reported here raises an important question: What happens to the remnants of RBCs undergoing spectosis? This is particularly crucial for maintaining bodily health, as the timely clearance of programmed cell death is essential for normal physiological management. Finally, the mechanisms underlying super hemolysis after transfusion have remained unknown for decades. However, since Chen et al. have characterized the intracellular signaling pathways of RBCs in hemolysis, it is possible that the NLRP3-ASC-caspase-8 pathway could be initiated by an unknown factor during super hemolysis following transfusion.
References
- Chen, Y., Chen, S., Liu, Z., Wang, Y., An, N., Chen, Y., Peng, Y., Liu, Z., Liu, Q., and Hu, X. (2025). Red blood cells undergo lytic programmed cell death involving NLRP3. Cell 188, 3013–3029. https://doi.org/10.1016/j.cell. 2025.03.039.
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- Panch, S.R., Montemayor-Garcia, C., and Klein, H.G. (2019). Hemolytic Transfusion Reactions. N. Engl. J. Med. 381, 150–162. https://doi.org/ 10.1056/NEJMra1802338.
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