Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes
Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes
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DOI：
10.1126/science.aao5213
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发表时间：
2019-01-11
期刊：
影响因子：
56.9
通讯作者：
Hamerman, Jessica A.
中科院分区：
文献类型：
--
作者：
Akilesh, Holly M.;Buechler, Matthew B.;Hamerman, Jessica A.
血细胞减少是与炎症性疾病和感染相关的重要临床问题。我们发现，在 Toll 样受体 7 (TLR7) 驱动的炎症中，会产生内化红细胞的专门吞噬细胞。 TLR7 信号传导导致炎症噬血细胞 (iHPC) 的发育，其类似于脾红髓巨噬细胞，但是源自 Ly6C(hi) 单核细胞的独特群体。 iHPC 是导致 TLR7 过表达小鼠贫血和血小板减少的原因，这些小鼠患有巨噬细胞激活综合征 (MAS) 样疾病。干扰素调节因子 5 (IRF5) 与 MAS 相关，参与 TLR7 驱动的 iHPC 分化。我们还在实验性疟疾贫血期间发现了 iHPC，其中它们需要内体 TLR 和 MyD88 信号传导进行分化。我们的研究结果揭示了 TLR7 和 TLR9 指定单核细胞命运的机制，并确定了负责与炎症和感染相关的贫血和血小板减少的特殊吞噬细胞群体。
Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6C(hi) monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.