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

doi:10.1016/j.celrep.2019.04.090

c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells

Cell Rep. 2019 May 21;27(8):2304-2312.e6. doi: 10.1016/j.celrep.2019.04.090.

Authors

Eric A Shikatani¹, Rickvinder Besla², Sherine Ensan³, Aditi Upadhye⁴, Nadiya Khyzha⁵, Angela Li³, Takuo Emoto⁵, Felix Chiu¹, Norbert Degousee⁵, Joshua M Moreau³, Heather M Perry⁴, Danya Thayaparan⁶, Henry S Cheng¹, Shaun Pacheco⁵, David Smyth⁵, Hossein Noyan⁵, Caleb C J Zavitz⁵, Carla M T Bauer⁷, Ingo Hilgendorf⁸, Peter Libby⁹, Filip K Swirski¹⁰, Jennifer L Gommerman³, Jason E Fish¹¹, Martin R Stampfli⁶, Myron I Cybulsky¹², Barry B Rubin¹³, Christopher J Paige¹⁴, Timothy P Bender¹⁵, Coleen A McNamara⁴, Mansoor Husain¹⁶, Clinton S Robbins¹⁷

Affiliations

¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada.
² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada. Electronic address: [email protected].
³ Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada.
⁴ Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA.
⁵ Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada.
⁶ McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S148, Canada.
⁷ Hoffmann-La Roche, pRED, Pharma Research & Early Development, DTA Inflammation, Nutley, NJ 07110, USA.
⁸ Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.
⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada.
¹² 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.
¹³ Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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. Electronic address: [email protected].

PMID: 31116977
DOI: 10.1016/j.celrep.2019.04.090

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibody-Producing Cells / immunology*
Antibody-Producing Cells / metabolism
Atherosclerosis / genetics*
Atherosclerosis / immunology*
Atherosclerosis / pathology
Bone Marrow Cells / immunology
Bone Marrow Cells / pathology
Genes, myb
Immunoglobulin M / metabolism*
Male
Mice
Proto-Oncogene Proteins c-myb / genetics*
Proto-Oncogene Proteins c-myb / immunology*

Substances

Immunoglobulin M
Proto-Oncogene Proteins c-myb

Abstract

Publication types

MeSH terms

Substances

Grants and funding