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ANIMAL MODELS

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

Leukemia volume 35, pages 3139–3151 (2021)Cite this article

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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.

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Fig. 1: Increased chemokines in the BM during SAA in mice.
Fig. 2: CCR5 expression is increased on macrophages during SAA.
Fig. 3: CCR5 antagonism with maraviroc improves survival and bone marrow cellularity when administered during SAA.
Fig. 4: The impact of CCR5 antagonism on T lymphocytes in SAA pathogenesis.
Fig. 5: CCR5 antagonism alters macrophage numbers and function during SAA.
Fig. 6: Intrinsic role for CCR5 in macrophages in SAA.
Fig. 7: Chemokines and their receptors in aged mice and humans.

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Acknowledgements

The authors would like to thank Angelica Costello and Hui Jin Jo for technical assistance. This work was supported by a Aplastic Anemia and MDS International Foundation grant to KCM, BM160071 and BM190079 (DOD-BMFRP-IDA) to KCM and R01 AG046293 to LMC.

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Author notes

  1. Amanda McCabe

    Present address: Boston Children’s Hospital TransLab, Translational Research Program, Boston, MA, USA

  2. Julianne N. P. Smith

    Present address: Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

Authors and Affiliations

  1. Department of Immunology and Microbiology, Albany Medical College, Albany, NY, USA

    Allison N. Seyfried, Amanda McCabe, Julianne N. P. Smith & Katherine C. MacNamara

  2. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA

    Laura M. Calvi

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ANS designed and performed experiments, analyzed data, and wrote the paper, AM and JNPS designed and performed experiments, and analyzed data, LMC designed experiments and analyzed data, and KCM conceived of the project, designed experiments, analyzed data, and wrote the paper.

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Correspondence to Katherine C. MacNamara.

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Seyfried, A.N., McCabe, A., Smith, J.N.P. et al. CCR5 maintains macrophages in the bone marrow and drives hematopoietic failure in a mouse model of severe aplastic anemia. Leukemia 35, 3139–3151 (2021). https://doi.org/10.1038/s41375-021-01219-z

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