Single cell RNA sequencing unravels mechanisms underlying senescence-like phenotypes of alveolar macrophages
Yue Wu,
Shengen Shawn Hu,
Ruixuan Zhang,
Nick P. Goplen,
Xiaochen Gao,
Harish Narasimhan,
Ao Shi,
Yin Chen,
Ying Li,
Chongzhi Zang,
Haidong Dong,
Thomas J. Braciale,
Bibo Zhu,
Jie Sun
Affiliations
Yue Wu
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Mayo Clinic Department of Immunology, Rochester, MN 55905, USA
Shengen Shawn Hu
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Ruixuan Zhang
Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
Nick P. Goplen
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
Xiaochen Gao
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Mayo Clinic Department of Immunology, Rochester, MN 55905, USA
Harish Narasimhan
Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
Ao Shi
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
Yin Chen
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Mayo Clinic Department of Immunology, Rochester, MN 55905, USA
Ying Li
Division of Computational Biology, Mayo Clinic, Rochester, MN 55905, USA
Chongzhi Zang
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA; UVA Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22908, USA
Haidong Dong
Mayo Clinic Department of Immunology, Rochester, MN 55905, USA; Department of Urology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Thomas J. Braciale
Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
Bibo Zhu
Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author
Jie Sun
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA; Mayo Clinic Department of Immunology, Rochester, MN 55905, USA; Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author
Summary: Alveolar macrophages (AMs) are resident innate immune cells that play vital roles in maintaining lung physiological functions. However, the effects of aging on their dynamics, heterogeneity, and transcriptional profiles remain to be fully elucidated. Through single cell RNA sequencing (scRNA-seq), we identified CBFβ as an indispensable transcription factor that ensures AM self-renewal. Intriguingly, despite transcriptome similarities of proliferating cells, AMs from aged mice exhibited reduced embryonic stem cell–like features. Aged AMs also displayed compromised DNA repair abilities, potentially leading to obstructed cell cycle progression and an elevation of senescence markers. Consistently, AMs from aged mice exhibited impaired self-renewal ability and reduced sensitivity to GM-CSF. Decreased CBFβ was observed in the cytosol of AMs from aged mice. Similar senescence-like phenotypes were also found in human AMs. Taken together, these findings suggest that AMs in aged hosts demonstrate senescence-like phenotypes, potentially facilitated by the abrogated CBF β activity.
