With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator of the cellular response to damage and stress is the transcription factor NF-κB. We demonstrated previously that NF-κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1-deficient mice). We also demonstrated that genetic reduction in the level of the NF-κB subunit p65(RelA) in the Ercc1−/∆ progeroid mouse model of accelerated aging delayed the onset of age-related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration. Here, we report that the largest fraction of NF-κB -expressing cells in the bone marrow (BM) of aged (>2 year old) mice (C57BL/6-NF-κBEGFP reporter mice) are Gr-1+CD11b+myeloid-derived suppressor cells (MDSCs). There was a significant increase in the overall percentage of MDSC present in the BM of aged animals compared with young, a trend also observed in the spleen. However, the function of these cells appears not to be compromised in aged mice. A similar increase of MDSC was observed in BM of progeroid Ercc1−/∆ and BubR1H/H mice. The increase in MDSC in Ercc1−/∆ mice was abrogated by heterozygosity in the p65/RelA subunit of NF-κB. These results suggest that NF-κB activation with aging, at least in part, drives an increase in the percentage of MDSCs, a cell type able to suppress immune cell responses.
Bibliographical noteFunding Information:
This work was supported by grants AG024827, AR051456, and AG043376 from the National Institutes of Health. R.R.F was supported by a T32 grant from NIH on Autoimmunity and Immunopathology. The authors would like to thank Dewayne Faulkner (University of Pittsburgh) for his assistance with flow cytometry and Joan Nash (University of Pittsburgh) for her administrative support. The authors would also like to thank Drs. Jing Zhao, Matthew Yousefzadeh, and Robert Brooks for their critical review of this manuscript.
© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
- myeloid-derived suppressor cell