CCR5 maintains macrophages in the bone marrow and drives hematopoietic failure in a mouse model of severe aplastic anemia.
CCR5 maintains macrophages in the bone marrow and drives hematopoietic failure in a mouse model of severe aplastic anemia.
复制标题
CCR5 维持骨髓中的巨噬细胞并导致严重再生障碍性贫血小鼠模型的造血衰竭。
DOI：
10.1038/s41375-021-01219-z
复制
发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
MacNamara KC
中科院分区：
文献类型：
--
作者：
Seyfried AN;McCabe A;Smith JNP;Calvi LM;MacNamara KC
重型再生障碍性贫血是一种获得性T细胞驱动的骨髓衰竭疾病，其特征是干扰素γ升高，造血干细胞丢失，骨髓微环境改变，包括功能障碍的巨噬细胞(MФS)。T淋巴细胞是治疗SAA的靶细胞，然而，推动SAA发生的潜在机制以及天然免疫细胞如何促进疾病仍然知之甚少。在SAA的小鼠模型中，增加的β-趋化因子与疾病相关，并部分依赖干扰素γ。干扰素γ是M-ФS细胞表面趋化因子受体CCR5表达增加所必需的，拮抗CCR5可提高小鼠存活率，其机制与增加血小板和显著增加偏向于血小板的CD41hi HSCs有关。T细胞是疾病的关键驱动力，然而，T细胞特异性CCR5的表达和T细胞来源的CCL5并不是疾病所必需的。CCR5拮抗剂降低骨髓ФS，减少其表达肿瘤坏死因子和CCL5，降低分泌干扰素γ的BM T细胞频率。从机制上讲，CCR5是在SAA期间维持BMФS的内在需要。老年小鼠和人的M-ФS的CCR5表达显著高于青年小鼠。我们的数据表明，CCR5信号是促进干扰素γ依赖的骨髓衰竭发生的关键轴，尤其与CCR5表达升高的衰老有关。
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 (MФs). 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 MФs. 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 MФs 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 MФs during SAA. Ccr5 expression was significantly increased in MФs 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.
登录
查看更多内容
影响因子：
7.3
作者：
Ghimire S;Weber D;Mavin E;Wang XN;Dickinson AM;Holler E
通讯作者：
Holler E
影响因子：
2.6
作者：
Chen, JC;Brandt, JS;Young, NS
通讯作者：
Young, NS
影响因子：
20.3
作者：
Machlus, Kellie R.;Johnson, Kelly E.;Battinelli, Elisabeth M.
通讯作者：
Battinelli, Elisabeth M.
DOI：
10.1046/j.1440-1746.2003.03088.x
发表时间：
2003-09-01
影响因子：
4.1
作者：
Matsuzaki, K;Hokari, R;Miura, S
通讯作者：
Miura, S
影响因子：
7.2
作者：
Halvorsen, E. C.;Hamilton, M. J.;Bennewith, K. L.
通讯作者：
Bennewith, K. L.