Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice
MetadataShow full item record
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.
Showing items related by title, author, creator and subject.
Jackaman, Connie; Dye, Danielle; Nelson, Delia (2014)The role of macrophages and their interactions with T cells during aging is not well understood. We determined if activating elderly-derived macrophages could rescue age-related and tumor-induced T cell dysfunction. Healthy ...
Jackaman, Connie; Tomay, Federica; Duong, Lelinh; Abdol Razak, Norbaini Bintu; Pixley, F.; Metharom, Pat; Nelson, Delia (2017)Impaired immune function has been implicated in the declining health and higher incidence of cancer in the elderly. However, age-related changes to immunity are not completely understood. Neutrophils and macrophages ...
Murine mesothelioma induces locally-proliferating IL-10<sup>+</sup>TNF-a<sup>+</sup>CD206<sup>-</sup>CX3CR1<sup>+</sup> M3 macrophages that can be selectively depleted by chemotherapy or immunotherapyJackaman, Connie; Yeoh, T.; Acuil, M.; Gardner, Joanne; Nelson, Delia (2016)© 2016 Taylor & Francis Group, LLC.We used a murine model to monitor changes to myeloid cell subsets, i.e., myeloid-derived suppressor cells (MDSCs), M1 macrophages that secrete pro-inflammatory cytokines and express CD40 ...