PDF(Pubmed)
Abstract：
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.
摘要：
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。尽管人们已经共同努力探索这些疾病的潜在发病机制，对致病突变的理解仍然不完整。在这里，我们在一个患病的谱系中确定了Toll样受体8（TLR8）的功能获得突变与遗传性非溶血性贫血有关。TLR8在红系谱系中表达,并且红细胞生成被TLR8激活损害,而被来自红系祖细胞阶段的TLR8抑制增强。机械上,TLR8激活阻断膜联蛋白A2(ANXA2)介导的STAT5的质膜定位并破坏HuDEP2细胞中的EPO信号传导。TLR8抑制改善了来自健康供体和遗传性非溶血性贫血患者的RPS19+/-HuDEP2细胞和CD34+细胞中的红细胞生成。总的来说，我们确定了一个与遗传性贫血有关的基因和以前未描述的TLR8在红细胞生成中的作用，这可能是潜在的探索遗传性贫血的治疗益处。
