Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice.
Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice.
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DOI：
10.26508/lsa.202302241
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发表时间：
2023-10
影响因子：
4.4
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中科院分区：
文献类型：
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人 TLR8 在易患狼疮的 Sle1.Yaa 小鼠的 BM 红细胞岛中央巨噬细胞中诱导炎症表型。无法支持红细胞前体粘附和发育会导致骨髓衰竭引起致命性贫血，随后在应激性红细胞生成过程中出现噬血作用。贫血通常发生在系统性红斑狼疮中，这是一种以核酸激活先天免疫为特征的疾病。自身 DNA 或 RNA 过度激活细胞质传感器可导致红系细胞死亡，同时不影响其他造血细胞谱系。尽管慢性炎症参与了这一机制，但人们对系统性红斑狼疮对 BM 红细胞生成生态位的影响知之甚少。我们发现内体 ssRNA 传感器人 TLR8 的表达会诱导 Sle1.Yaa 狼疮小鼠致命性贫血。我们观察到贫血与红骨髓细胞岛的减少以及 BM 中 CFU-E 向原红细胞转变的分化受阻有关。对表达人 TLR8 的小鼠分离的 BM 红骨髓细胞岛进行的单细胞 RNAseq 分析表明，与重要的中央巨噬细胞功能（包括粘附和营养供应）相关的基因被下调。尽管脾脏中发生代偿性应激性红细胞生成，但由于噬血作用，红细胞半衰期缩短。这些数据表明内体 RNA 传感器 TLR8 作为一种额外的先天受体，其过度激活会通过骨髓细胞失调导致获得性红细胞生成失败。
Human TLR8 induces an inflammatory phenotype in BM erythroblastic island central macrophages of lupus-prone Sle1.Yaa mice. Failure to support erythroid precursor adhesion and development induces fatal anemia caused by bone marrow failure followed by hemophagocytosis during stress erythropoiesis. Anemia commonly occurs in systemic lupus erythematosus, a disease characterized by innate immune activation by nucleic acids. Overactivation of cytoplasmic sensors by self-DNA or RNA can cause erythroid cell death, while sparing other hematopoietic cell lineages. Whereas chronic inflammation is involved in this mechanism, less is known about the impact of systemic lupus erythematosus on the BM erythropoietic niche. We discovered that expression of the endosomal ssRNA sensor human TLR8 induces fatal anemia in Sle1.Yaa lupus mice. We observed that anemia was associated with a decrease in erythromyeloblastic islands and a block in differentiation at the CFU-E to proerythroblast transition in the BM. Single-cell RNAseq analyses of isolated BM erythromyeloblastic islands from human TLR8-expressing mice revealed that genes associated with essential central macrophage functions including adhesion and provision of nutrients were down-regulated. Although compensatory stress erythropoiesis occurred in the spleen, red blood cell half-life decreased because of hemophagocytosis. These data implicate the endosomal RNA sensor TLR8 as an additional innate receptor whose overactivation causes acquired failure of erythropoiesis via myeloid cell dysregulation.