Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease
Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease
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DOI：
10.1182/blood.2021011629
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发表时间：
2021-09-30
期刊：
影响因子：
20.3
通讯作者：
Yazdanbakhsh, Karina
中科院分区：
文献类型：
--
作者：
Liu, Yunfeng;Pal, Mouli;Yazdanbakhsh, Karina
镰状细胞病(SCD)患者遭受血管溶血相关的血管损伤和组织损伤。经典单核细胞(CMO)是循环中最丰富的单核细胞，在SCD中被激活，但激活的原因和后果仍不完全清楚。通过转录组分析发现，SCD患者血浆总血红素水平与循环干扰素-α(IFN-α)水平呈正相关，SCD患者CMO经分类纯化后，I型干扰素(IFN-I)诱导基因表达上调。我们证明，溶血导致干扰素-I的表达，主要是通过小鼠肝脏单核细胞和巨噬细胞(M Phi)，主要是通过Tank Kinase Binding1(TBK1)/I kappa B Kinase-epsilon(Ikk Epsilon)而不是TLR4。作为对溶血诱导的干扰素-I的反应，小鼠CMO迁移到肝脏并分化为单核细胞来源的MF，在急性氯化血红素治疗下，它们的数量增加了6倍。溶血驱动的干扰素-I活性还可诱导单核细胞和MF群体表达Fc受体CD64，从而增强同种异体抗体在体内和体外培养的SCD中的红细胞吞噬作用。总之，这些数据表明，在单核细胞中，干扰素-I对溶血的反应是一种新的激活途径，而在SCD中，MF是一种新的激活途径，这为基于干扰素-I的针对同种抗体介导的红细胞吞噬症的诊断和治疗开辟了可能性。
Patients with sickle cell disease (SCD) suffer fromintravascular hemolysis-associated vascular injury and tissue damage. Classical monocytes (CMo), which are the most abundant of circulating monocytes, are activated in SCD, but the cause and consequences of activation remain incompletely understood. We found a positive correlation between total plasma heme levels and circulating interferon-alpha (IFN-alpha) in patients with SCD along with upregulation of the type I IFN (IFN-I) inducible genes in sort-purified SCD patients' CMo by transcriptome analysis. We demonstrated that hemolysis led to IFN-I expression, predominantly by mouse liver monocyte and macrophages (M phi), primarily through Tank kinase binding 1 (TBK1)/I kappa B kinase-epsilon (IKK epsilon) but not TLR4. In response to hemolysis-induced IFN-I, mouse CMo migrated to the liver and differentiated into monocyte-derived Mf, increasing their numbers by sixfold with acute hemin treatment. Hemolysis-driven IFN-I activity also led to the induction of Fc receptor CD64 expression on monocyte and Mf populations, enhancing alloantibody-mediated erythrophagocytosis in SCD both in vivo in mice and in in vitro human cultures. Altogether, these data demonstrate IFN-I response to hemolysis as a novel activation pathway in monocytes and Mf in SCD, opening the possibility for development of IFN-I-based diagnostics and therapeutics against alloantibodymediated erythrophagocytosis.