title: Expansion of myeloid-derived suppressor cells with aging in the bone marrow of mice through a NF-κB-dependent mechanism.
abstract: 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-κBEGFPreporter 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/Hmice. 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.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, 33458, USA.
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Flores
authors.affiliation: Molecular Genetic and Microbiology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Clauson
authors.affiliation: Molecular Genetic and Microbiology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.|Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA.
authors.forename: Joonseok
authors.initials: J
authors.lastname: Cho
authors.affiliation: Molecular Genetic and Microbiology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.|Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA.
authors.forename: Byeong-Chel
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, 33458, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, 33458, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, 33458, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D004720:Endonucleases; C499360:Ercc1 protein, mouse
keywords: NF-κB; myeloid-derived suppressor cell; senescence