| First Author | Seyfried AN | Year | 2021 |
| Journal | Leukemia | Volume | 35 |
| Issue | 11 | Pages | 3139-3151 |
| PubMed ID | 33744909 | Mgi Jnum | J:318646 |
| Mgi Id | MGI:6784159 | Doi | 10.1038/s41375-021-01219-z |
| Citation | Seyfried AN, et al. (2021) CCR5 maintains macrophages in the bone marrow and drives hematopoietic failure in a mouse model of severe aplastic anemia. Leukemia 35(11):3139-3151 |
| abstractText | Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFNgamma), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (MPhis). 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 IFNgamma. IFNgamma was required for increased expression of the chemokine receptor CCR5 on MPhis. 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 MPhis and diminished their expression of Tnf and Ccl5, correlating with reduced frequencies of IFNgamma-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM MPhis during SAA. Ccr5 expression was significantly increased in MPhis from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFNgamma-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated. |
