Macrophage-Mediated HSC Dysfunction in Bone Marrow Failure
Abstract
Aplastic anemia is the rare, but devastating, collapse of blood production, and if left untreated, the disease is invariably fatal. Our current therapies are inadequate in the sense that they involve general immunosuppression or highly invasive and risky bone marrow transplantation. The causes of this severe form of bone marrow failure include both genetic mutations and exposure to chemicals or infectious agents. In both genetic and acquired cases, excessive inflammation ultimately causes destruction of the stem cells required to maintain daily production of all blood cells. Inflammatory molecules such as interferon gamma (IFN-gamma) are known to contribute to pathology, yet exactly how stem cell function is compromised by these factors is not clear and remains an important question in understanding the pathogenesis of bone marrow failure. We utilized a mouse model of aplastic anemia to investigate the mechanisms whereby IFN-gamma drives hematopoietic failure. We made the unexpected observation that IFN-gamma signaling in stem cells themselves was not required for the loss of blood stem cells. We identified macrophages, key phagocytic cells of the immune system, as the direct targets of IFN-gamma in driving the decline of stem cells during bone marrow failure. Ablation of the macrophage population during disease preserved stem cell function and prevented death caused by hematopoietic failure. Preventing IFN-gamma signaling exclusively in macrophages was also able to rescue disease. We identified two novel mechanisms whereby IFN-gamma and macrophages drive HSC loss. First, the chemokine CCL5 is robustly produced and requires both IFN-gamma and macrophages. Second, macrophages aberrantly express the cell surface protein podoplanin. Neutralization of either factor can increase the number of HSCs in aplastic anemia. Thus, we propose to test the hypothesis that macrophages drive HSC loss through CCL5 and podoplanin expression. Herein, we proposed to determine (1) the impact of podoplanin and CCL5 on quiescent HSC niche cells and (2) whether reducing macrophages (and their associated factors) can rescue severe bone marrow failure in a mouse model. Although macrophage activity has been previously associated with hematologic disorders, we have little understanding of how macrophages regulate stem cell activity. Macrophages are important components of the innate immune system and also regulate many processes, such as the formation of new blood vessels and clearance of dead or dying cells. The sensitivity of macrophages to cytokines, in particular IFN-gamma, is exquisite, and their function can be drastically altered by their microenvironment. They are first responders to environmental stimuli, including pathogens and chemicals, which are known triggers for acquired bone marrow failure. These facts and our preliminary data provide strong rationale to investigate the therapeutic efficacy of reducing macrophages for treatment of aplastic anemia. There are clinical trials currently underway aimed at reducing macrophages in other inflammatory diseases, such as rheumatoid arthritis and cancer. Therefore, the proposed studies have immediate translational relevance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710199
Entities
People
- Katherine C MacNamara
Organizations
- Albany Medical College
- United States Army