title: Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.
abstract: Bone marrow (BM) resident macrophages (Mϕs) regulate hematopoietic stem cell (HSC) mobilization; however, their impact on HSC function has not been investigated. We demonstrate that depletion of BM resident Mϕs increases HSC proliferation as well as the pool of quiescent HSCs. At the same time, during bacterial infection where BM resident Mϕs are selectively increased we observe a decrease in HSC numbers. Moreover, strategies that deplete or reduce Mϕs during infection prevent HSC loss and rescue HSC function. We previously found that the transient loss of HSCs during infection is interferon-gamma (IFNγ)-dependent. We now demonstrate that IFNγ signaling specifically in Mϕs is critical for both the diminished HSC pool and maintenance of BM resident Mϕs during infection. In addition to the IFNγ-dependent loss of BM HSC and progenitor cells (HSPCs) during infection, IFNγ reduced circulating HSPC numbers. Importantly, under infection conditions AMD3100 or G-CSF-induced stem cell mobilization was impaired. Taken together, our data show that IFNγ acts on Mϕs, which are a negative regulator of the HSC pool, to drive the loss in BM and peripheral HSCs during infection. Our findings demonstrate that modulating BM resident Mϕ numbers can impact HSC function in vivo, which may be therapeutically useful for hematologic conditions and refinement of HSC transplantation protocols.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: McCabe
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Vinh
authors.initials: V
authors.lastname: Thai
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Jones
authors.affiliation: Division of Cellular and Molecular Immunology, Cincinnati Children's Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: MacNamara
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D007371:Interferon-gamma
keywords: Hematopoietic stem cells; Interferon-gamma; Macrophages