CCR5 maintains macrophages in the bone marrow and drives hematopoietic failure in a mouse model of severe aplastic anemia

Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFN gamma), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (M phi s). 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 IFN gamma. IFN gamma was required for increased expression of the chemokine receptor CCR5 on M phi s. CCR5 antagonism in murine SAA improved survival, correlating with increased platelets and significantly increased platelet-biased CD41(hi) 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 M phi s and diminished their expression of Tnf and Ccl5, correlating with reduced frequencies of IFN gamma-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM M phi s during SAA. Ccr5 expression was significantly increased in M phi s from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFN gamma-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated.

Automated summary

Our research has identified CCR5 signaling as a key axis promoting the development of IFN gamma-dependent bone marrow failure, particularly relevant in aging where Ccr5 expression is elevated.