Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression

Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFN gamma) 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 IFN gamma-dependent hematopoietic stem cell loss required macrophages. IFN gamma was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFN gamma signaling specifically in macrophages did not impair T-cell activation or IFN gamma production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFN gamma in SAA and rather act as sensors of IFN gamma. 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 nonhematopoietic 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 IFN gamma, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.