Macrophage-Mediated HSC Dysfunction in Bone Marrow Failure
Abstract
Interferon-gamma (IFNgamma) is increased in patients with a type of bone marrow failure (BMF) called aplastic anemia (AA). IFNgamma has been linked with hematopoietic dysfunction and exhaustion of hematopoietic stem cells (HSCs). However, it is still unclear how IFNgamma drives BMF. HSCs are rare, multipotent cells residing in the BM that give rise to all cells of the blood. The BM microenvironment, or HSC niche, plays a key role in blood cell production by controlling HSC function and maintaining HSCs in a quiescent state, necessary for their self-renewal and life-long blood production. Macrophages (Ms) are myeloid cells that maintain tissue homeostasis throughout the body and also play a key rolein initiating innate immunity and countering infection. They respond to, and produce, many factors that direct host immune responses, and their function is highly plastic. In fact, recent evidence suggests that at steady-state Ms are important for maintaining HSC dormancy, yet how inflammation impacts M function and HSC maintenance is not yet clear. Notably, Ms are exquisitely sensitive to IFNgamma. We found that Ms are required for the IFNgamma-dependent loss of HSCs in a mouse model of AA and depletion of Ms increases HSC self-renewal (McCabe et al., 2015). Thus, in contrast to the assumption that IFNgamma acts directly on HSCs to drive their loss, Ms are the key cellular targets of IFNgamma. We also identified the chemokine CCL5 as an IFN- dependent chemokine responsible for HSC loss. Moreover, Ms aberrantly express podoplanin (PDPN) during AA and this signaling is also important for mediating HSC loss in AA. The rationale for this proposal is that Ms are essential targets of IFNgamma and control numbers of HSCs in vivo, in part via CCL5 and PDPN expression thus, suggesting novel therapeutic targets for treatment of AA.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2018
- Accession Number
- AD1094233
Entities
People
- Katherine C MacNamara
Organizations
- Albany Medical College