• Open Access

Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice

Authors

  • Connie Jackaman,

    Corresponding author
    1. School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Perth, WA, Australia
    • Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, WA, Australia
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  • Hannah G. Radley-Crabb,

    1. School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Perth, WA, Australia
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  • Zoe Soffe,

    1. School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, WA, Australia
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  • Tea Shavlakadze,

    1. School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, WA, Australia
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  • Miranda D. Grounds,

    1. School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, WA, Australia
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  • Delia J. Nelson

    1. Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, WA, Australia
    2. School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University, Perth, WA, Australia
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Correspondence

Dr. Connie Jackaman, c/o School of Biomedical Sciences, Curtin University, Kent St., Bentley, Perth WA 6102, Australia. Tel.: +618 9266 9713; fax: +618 9266 2342; e-mail: Connie.Jackaman@curtin.edu.au

Summary

Changes to innate cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), during aging in healthy or tumor-bearing hosts are not well understood. We compared macrophage subpopulations and MDSCs from healthy young (6–8 weeks) C57BL/6J mice to those from healthy geriatric (24–28 months) mice. Spleens, lymph nodes, and bone marrow of geriatric hosts contained significantly more M2 macrophages and MDSCs than their younger counterparts. Peritoneal macrophages from geriatric, but not young, mice co-expressed CD40 and CX3CR1 that are usually mutually exclusively expressed by M1 or M2 macrophages. Nonetheless, macrophages from geriatric mice responded to M1 or M2 stimuli similarly to macrophages from young mice, although they secreted higher levels of TGF-β in response to IL-4. We mimicked conditions that may occur within tumors by exposing macrophages from young vs. geriatric mice to mesothelioma or lung carcinoma tumor cell–derived supernatants. While both supernatants skewed macrophages toward the M2-phenotype regardless of age, only geriatric-derived macrophages produced IL-4, suggesting a more immunosuppressive tumor microenvironment will be established in the elderly. Both geriatric- and young-derived macrophages induced allogeneic T-cell proliferation, regardless of the stimuli used, including tumor supernatant. However, only macrophages from young mice induced T-cell IFN-γ production. We examined the potential of an IL-2/agonist anti-CD40 antibody immunotherapy that eradicates large tumors in young hosts to activate macrophages from geriatric mice. IL-2-/CD40-activated macrophages rescued T-cell production of IFN-γ in geriatric mice. Therefore, targeting macrophages with IL-2/anti-CD40 antibody may improve innate and T-cell immunity in aging hosts.

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