Abstract
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 podo...Continue Reading
Citations
Oct 27, 2018·Blood·Wanling SunNeal S Young
Feb 5, 2019·Journal of Cellular Physiology·Xu-Ling LuoLin-Xi Chen
Dec 21, 2018·Frontiers in Oncology·Michael MedingerJakob Passweg
Apr 19, 2019·JCI Insight·Benjamin J FrischLaura M Calvi
Jan 25, 2020·Cellular and Molecular Life Sciences : CMLS·Xinxin YangBo Zhu
Aug 28, 2020·Frontiers in Immunology·Allison N SeyfriedKatherine C MacNamara
Dec 1, 2020·International Journal of Radiation Biology·Wen JuLingyu Zeng
Jan 7, 2021·Cancers·Bruno FattizzoChiara Caprioli
Mar 13, 2021·PloS One·Sabrina SolorzanoNeal S Young
Feb 19, 2021·JCI Insight·Julianne Np SmithAmar B Desai
Mar 22, 2021·Leukemia·Allison N SeyfriedKatherine C MacNamara
May 19, 2020·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Julianne N P SmithAmar B Desai
Jul 24, 2021·Experimental Hematology·Jean-Pierre LévesqueAllison R Pettit
Aug 19, 2021·Cell Biology International·Mohammad R JavanBahareh Moghimian-Boroujeni
Aug 28, 2021·European Journal of Medicinal Chemistry·Ziqian ZhangTengfei Ji