Department for Immunology and Microbial Disease, Albany Medical College, NY, USA.
Department for Immunology and Microbial Disease, Albany Medical College, NY, USA
Haematologica. 2018 Sep;103(9):1451-1461. doi: 10.3324/haematol.2018.189449. Epub 2018 May 17.
Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFNγ) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFNγ-dependent hematopoietic stem cell loss required macrophages. IFNγ was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFNγ signaling specifically in macrophages did not impair T-cell activation or IFNγ production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFNγ in SAA and rather act as sensors of IFNγ. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, SAA induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis, demonstrating a novel role for macrophages as sensors of IFNγ, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.
重型再生障碍性贫血（SAA）是由严重的造血干细胞损失引起的。T 细胞和干扰素γ（IFNγ）长期以来与 SAA 有关，但导致造血干细胞损失的潜在机制仍不清楚。使用 SAA 的小鼠模型，我们证明了 IFNγ 依赖性造血干细胞损失需要巨噬细胞。尽管其他髓样细胞和造血干细胞丢失，IFNγ 仍对骨髓巨噬细胞的持续存在是必需的。耗尽巨噬细胞或特异性地在巨噬细胞中阻断 IFNγ 信号传导不会损害骨髓中的 T 细胞激活或 IFNγ 产生，但可挽救造血干细胞并降低死亡率。因此，巨噬细胞对于 SAA 中的 IFNγ 诱导不是必需的，而是作为 IFNγ 的传感器起作用。巨噬细胞耗竭可挽救血小板减少症，增加骨髓巨核细胞，保存血小板激活的干细胞，并增加移植造血干细胞的血小板再殖能力。除了造血作用外，SAA 还导致非造血基质群体的损失，包括 podoplanin 阳性基质细胞。然而，疾病期间 podoplanin 阳性巨噬细胞的亚群增加，并且在小鼠中阻断 podoplanin 足以挽救疾病。我们的数据进一步了解了疾病的发病机制，证明了巨噬细胞作为 IFNγ 传感器的新作用，从而说明了微环境在 SAA 发病机制中的重要作用。
