Abstract
Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFNγ), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (MΦs). T lymphocytes are therapeutic targets for treating SAA, however, the underlying mechanisms driving SAA development and how innate immune cells contribute to disease remain poorly understood. In a murine model of SAA, increased beta-chemokines correlated with disease and were partially dependent on IFNγ. IFNγ was required for increased expression of the chemokine receptor CCR5 on MΦs. CCR5 antagonism in murine SAA improved survival, correlating with increased platelets and significantly increased platelet-biased CD41hi HSCs. T cells are key drivers of disease, however, T cell-specific CCR5 expression and T cell-derived CCL5 were not necessary for disease. CCR5 antagonism reduced BM MΦs and diminished their expression of Tnf and Ccl5, correlating with reduced frequencies of IFNγ-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM MΦs during SAA. Ccr5 expression was significantly increased in MΦs from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFNγ-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated.