Cell Reports (May 2019)
c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells
- Eric A. Shikatani,
- Rickvinder Besla,
- Sherine Ensan,
- Aditi Upadhye,
- Nadiya Khyzha,
- Angela Li,
- Takuo Emoto,
- Felix Chiu,
- Norbert Degousee,
- Joshua M. Moreau,
- Heather M. Perry,
- Danya Thayaparan,
- Henry S. Cheng,
- Shaun Pacheco,
- David Smyth,
- Hossein Noyan,
- Caleb C.J. Zavitz,
- Carla M.T. Bauer,
- Ingo Hilgendorf,
- Peter Libby,
- Filip K. Swirski,
- Jennifer L. Gommerman,
- Jason E. Fish,
- Martin R. Stampfli,
- Myron I. Cybulsky,
- Barry B. Rubin,
- Christopher J. Paige,
- Timothy P. Bender,
- Coleen A. McNamara,
- Mansoor Husain,
- Clinton S. Robbins
Affiliations
- Eric A. Shikatani
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
- Rickvinder Besla
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Corresponding author
- Sherine Ensan
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
- Aditi Upadhye
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
- Nadiya Khyzha
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Angela Li
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
- Takuo Emoto
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Felix Chiu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
- Norbert Degousee
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Joshua M. Moreau
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
- Heather M. Perry
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
- Danya Thayaparan
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S148, Canada
- Henry S. Cheng
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
- Shaun Pacheco
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- David Smyth
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Hossein Noyan
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Caleb C.J. Zavitz
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Carla M.T. Bauer
- Hoffmann-La Roche, pRED, Pharma Research & Early Development, DTA Inflammation, Nutley, NJ 07110, USA
- Ingo Hilgendorf
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
- Peter Libby
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Filip K. Swirski
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Jennifer L. Gommerman
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
- Jason E. Fish
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
- Martin R. Stampfli
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S148, Canada
- Myron I. Cybulsky
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada
- Barry B. Rubin
- Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada
- Christopher J. Paige
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2M9, Canada
- Timothy P. Bender
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA; Beirne B. Carter Center for Immunology Research, University of Virginia Health System, Charlottesville, VA 22903, USA
- Coleen A. McNamara
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
- Mansoor Husain
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2M9, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada; McEwen Centre for Regenerative Medicine, Toronto, ON, Canada
- Clinton S. Robbins
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 8
pp. 2304 – 2312.e6
Abstract
Summary: Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease. : Shikatani et al. demonstrate that the nuclear transcription factor c-Myb exacerbates experimental atherosclerosis directly through its effects on B lymphocytes. Paradoxically, c-Myb promotes B2 cell development yet limits numbers of IgM-producing antibody-secreting cells and levels of atheroprotective OxLDL-specific IgM antibodies.
