State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tianjin Institutes of Health Science, Tianjin, 301600, China.
Nat Commun. 2024 Jul 6;15(1):5678. doi: 10.1038/s41467-024-50066-w.
Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19 HuDEP2 cells and CD34 cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.
遗传性非溶血性贫血是一组以红系缺陷为特征的罕见骨髓疾病。尽管已经做出了协同努力来探索这些疾病的潜在发病机制，但对致病突变的理解仍然不完整。在这里，我们在一个患病家族中发现，Toll 样受体 8（TLR8）的功能获得性突变与遗传性非溶血性贫血有关。TLR8 在红系谱系中表达，并且 TLR8 的激活会损害红细胞生成，而从红细胞祖细胞阶段开始抑制 TLR8 则会增强红细胞生成。在机制上，TLR8 的激活会阻止膜联蛋白 A2（ANXA2）介导的 STAT5 向质膜的定位，并破坏 HuDEP2 细胞中的 EPO 信号。TLR8 抑制可改善 RPS19 HuDEP2 细胞和来自健康供体和遗传性非溶血性贫血患者的 CD34 细胞的红细胞生成。总的来说，我们确定了一个与遗传性贫血相关的基因，并发现了 TLR8 在红细胞生成中的一个以前未描述的作用，这可能为遗传性贫血的治疗带来益处。
