Immunology Program, Benaroya Research Institute, Seattle, WA, USA.
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA.
Science. 2019 Jan 11;363(6423). doi: 10.1126/science.aao5213.
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 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.
血细胞减少症是与炎症性疾病和感染相关的一个重要临床问题。我们表明，可内化红细胞的特化吞噬细胞在 Toll 样受体 7（TLR7）驱动的炎症中发育。TLR7 信号导致炎症性噬血细胞（iHPC）的发育，其类似于脾红髓巨噬细胞，但却是源自 Ly6C 单核细胞的一个独特群体。iHPC 是 TLR7 过表达小鼠贫血和血小板减少症的原因，这些小鼠具有类似于巨噬细胞活化综合征（MAS）的疾病。与 MAS 相关的干扰素调节因子 5（IRF5）参与了 TLR7 驱动的 iHPC 分化。我们还在实验性疟原虫贫血中发现了 iHPC，在这种情况下，它们需要内体 TLR 和 MyD88 信号来进行分化。我们的发现揭示了 TLR7 和 TLR9 决定单核细胞命运的机制，并鉴定了负责与炎症和感染相关的贫血和血小板减少症的专门吞噬细胞群体。
