Chang Che-Yu, Hernández-Armengol Rosario, Paul Kausik, Lee June Young, Nance Karina, Shibata Tomohiro, Yue Peibin, Stehlik Christian, Gibb David R
bioRxiv. 2025 Apr 6:2025.04.03.645598. doi: 10.1101/2025.04.03.645598.
During red blood cell (RBC) transfusion, production of alloantibodies can promote significant hemolytic events. However, most transfusion recipients do not form anti-RBC alloantibodies. Identifying mechanisms that inhibit alloimmunization may lead to prophylactic interventions. One potential regulatory mechanism is activation of the transcription factor, nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulatory of antioxidant pathways. Pharmacologic Nrf2 activators improve sequelae of sickle cell disease in pre-clinical models. The Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), suppresses production of inflammatory cytokines including type 1 interferons (IFNα/β), which have been implicated in promoting RBC alloimmunization in transfusion models. Thus, we tested the hypothesis that the Nrf2 activator, CDDO-Im, regulates RBC alloimmunization. Here, we report that CDDO-Im induced Nrf2 activated gene expression and suppressed poly(I:C)-induced IFNα/β-stimulated gene (ISG) expression in human macrophages and murine blood leukocytes. In addition, following transfusion of wildtype mice with RBCs expressing the KEL antigen, CDDO-Im treatment inhibited poly(I:C)-induced anti-KEL IgG production and promoted post-transfusion recovery of KEL+ RBCs, but failed to do so in mice. Results indicate that activation of the Nrf2 antioxidant pathway regulates RBC alloimmunization to the KEL antigen in a pre-clinical model. If findings translate to other models and human studies, Nrf2 activators may represent a potential prophylactic intervention to inhibit alloimmunization.
The antioxidant pathway, Nrf2, inhibits anti-RBC alloantibody responses in a pre-clinical transfusion model.Nrf2 activation may represent a prophylactic strategy to inhibit RBC alloimmunization in transfusion recipients.
在红细胞（RBC）输血过程中，同种抗体的产生可引发严重的溶血事件。然而，大多数输血受者并不会形成抗RBC同种抗体。确定抑制同种免疫的机制可能会带来预防性干预措施。一种潜在的调节机制是转录因子核因子红系衍生2样2（Nrf2）的激活，Nrf2是抗氧化途径的主要调节因子。在临床前模型中，Nrf2的药理学激活剂可改善镰状细胞病的后遗症。Nrf2激活剂1-[2-氰基-3-，12-二氧代齐墩果-1，9（11）-二烯-28-酰基]咪唑（CDDO-Im）可抑制包括1型干扰素（IFNα/β）在内的炎性细胞因子的产生，在输血模型中，1型干扰素与促进RBC同种免疫有关。因此，我们测试了Nrf2激活剂CDDO-Im调节RBC同种免疫的假说。在此，我们报告CDDO-Im在人巨噬细胞和小鼠血液白细胞中诱导Nrf2激活基因表达并抑制聚肌苷酸-聚胞苷酸（poly(I:C)）诱导的IFNα/β刺激基因（ISG）表达。此外，在用表达KEL抗原的RBC输注野生型小鼠后，CDDO-Im处理可抑制poly(I:C)诱导的抗KEL IgG产生，并促进KEL+ RBC的输血后恢复，但在Nrf2基因敲除小鼠中则无效。结果表明，在临床前模型中，Nrf2抗氧化途径的激活可调节对KEL抗原的RBC同种免疫。如果研究结果能转化到其他模型和人体研究中，Nrf2激活剂可能代表一种抑制同种免疫的潜在预防性干预措施。
抗氧化途径Nrf2在临床前输血模型中抑制抗RBC同种抗体反应。Nrf2激活可能代表一种抑制输血受者RBC同种免疫的预防策略。
