Department of Immunology and Microbiology, Albany Medical College, Albany, NY, USA.
Boston Children's Hospital TransLab, Translational Research Program, Boston, MA, USA.
Leukemia. 2021 Nov;35(11):3139-3151. doi: 10.1038/s41375-021-01219-z. Epub 2021 Mar 20.
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 CD41 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.
重型再生障碍性贫血（SAA）是一种获得性、T 细胞驱动的骨髓（BM）衰竭疾病，其特征是干扰素γ（IFNγ）升高、造血干细胞（HSCs）丢失以及 BM 微环境改变，包括功能失调的巨噬细胞（MΦs）。T 淋巴细胞是治疗 SAA 的治疗靶点，然而，导致 SAA 发展的潜在机制以及先天免疫细胞如何导致疾病仍知之甚少。在 SAA 的小鼠模型中，β趋化因子的增加与疾病相关，并且部分依赖于 IFNγ。IFNγ是 MΦ上趋化因子受体 CCR5 表达增加所必需的。在 SAA 的小鼠中，CCR5 拮抗剂可改善存活率，与血小板增加和显著增加偏向血小板的 CD41 HSCs 相关。T 细胞是疾病的关键驱动因素，然而，T 细胞特异性 CCR5 表达和 T 细胞衍生的 CCL5 对于疾病并非必需。CCR5 拮抗剂减少了 BM MΦs，并降低了其 TNF 和 Ccl5 的表达，与 IFNγ 分泌的 BM T 细胞频率降低相关。从机制上讲，CCR5 在 SAA 期间固有地维持 BM MΦs。与年轻的对应物相比，来自老年小鼠和人类的 MΦs 中 Ccr5 的表达显著增加。我们的数据表明，CCR5 信号作为促进 IFNγ 依赖性 BM 衰竭发展的关键轴，在衰老时 Ccr5 表达升高时尤为相关。
