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

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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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. 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.

Original language	English (US)
Pages (from-to)	2304-2312.e6
Journal	Cell Reports
Volume	27
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2019.04.090
State	Published - May 21 2019
Externally published	Yes

Funding

We would like to acknowledge the administrative assistance of Bani Bali. This work was supported by a CIHR New Investigator Award ( MSH136670 ), the CIHR ( MOP133390 and PJT153085 ), an Ontario Lung Association/Pfizer Award , and the Peter Munk Chair in Aortic Disease Research (C.S.R.). This research is part of the University of Toronto’s Medicine by Design initiative, which receives funding from the Canada First Research Excellence Fund (CFREF). M.H. is a Career Investigator of the Heart and Stroke Foundation of Ontario ( CI5503 ) and supported by the CIHR ( MOP136850 ). E.A.S. was supported by a CIHR SHOPP PA: Hypertension Doctoral Research Award and a Meredith & Malcolm Silver Scholarship in Cardiovascular Studies . R.B. and S.E. were supported by Ontario Graduate Scholarships .

Funders	Funder number
Canadian Institutes of Health Research	MSH136670, MOP136850, PJT153085, MOP133390
Heart and Stroke Foundation Canada	CI5503
Toronto Western Hospital and University of Toronto
Canada First Research Excellence Fund

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2019.04.090

Cite this

Shikatani, E. A., Besla, R., Ensan, S., Upadhye, A., Khyzha, N., Li, A., Emoto, T., Chiu, F., Degousee, N., Moreau, J. M., Perry, H. M., Thayaparan, D., Cheng, H. S., Pacheco, S., Smyth, D., Noyan, H., Zavitz, C. C. J., Bauer, C. M. T., Hilgendorf, I., ... Robbins, C. S. (2019). c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells. Cell Reports, 27(8), 2304-2312.e6. https://doi.org/10.1016/j.celrep.2019.04.090

Shikatani, EA, Besla, R, Ensan, S, Upadhye, A, Khyzha, N, Li, A, Emoto, T, Chiu, F, Degousee, N, Moreau, JM, Perry, HM, Thayaparan, D, Cheng, HS, Pacheco, S, Smyth, D, Noyan, H, Zavitz, CCJ, Bauer, CMT, Hilgendorf, I, Libby, P, Swirski, FK, Gommerman, JL, Fish, JE, Stampfli, MR, Cybulsky, MI, Rubin, BB, Paige, CJ, Bender, TP, McNamara, CA, Husain, M & Robbins, CS 2019, 'c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells', Cell Reports, vol. 27, no. 8, pp. 2304-2312.e6. https://doi.org/10.1016/j.celrep.2019.04.090

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title = "c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells",

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. 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.",

author = "Shikatani, \{Eric A.\} and Rickvinder Besla and Sherine Ensan and Aditi Upadhye and Nadiya Khyzha and Angela Li and Takuo Emoto and Felix Chiu and Norbert Degousee and Moreau, \{Joshua M.\} and Perry, \{Heather M.\} and Danya Thayaparan and Cheng, \{Henry S.\} and Shaun Pacheco and David Smyth and Hossein Noyan and Zavitz, \{Caleb C.J.\} and Bauer, \{Carla M.T.\} and Ingo Hilgendorf and Peter Libby and Swirski, \{Filip K.\} and Gommerman, \{Jennifer L.\} and Fish, \{Jason E.\} and Stampfli, \{Martin R.\} and Cybulsky, \{Myron I.\} and Rubin, \{Barry B.\} and Paige, \{Christopher J.\} and Bender, \{Timothy P.\} and McNamara, \{Coleen A.\} and Mansoor Husain and Robbins, \{Clinton S.\}",

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doi = "10.1016/j.celrep.2019.04.090",

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AU - Shikatani, Eric A.

AU - Besla, Rickvinder

AU - Ensan, Sherine

AU - Upadhye, Aditi

AU - Khyzha, Nadiya

AU - Li, Angela

AU - Emoto, Takuo

AU - Chiu, Felix

AU - Degousee, Norbert

AU - Moreau, Joshua M.

AU - Perry, Heather M.

AU - Thayaparan, Danya

AU - Cheng, Henry S.

AU - Pacheco, Shaun

AU - Smyth, David

AU - Noyan, Hossein

AU - Zavitz, Caleb C.J.

AU - Bauer, Carla M.T.

AU - Hilgendorf, Ingo

AU - Libby, Peter

AU - Swirski, Filip K.

AU - Gommerman, Jennifer L.

AU - Fish, Jason E.

AU - Stampfli, Martin R.

AU - Cybulsky, Myron I.

AU - Rubin, Barry B.

AU - Paige, Christopher J.

AU - Bender, Timothy P.

AU - McNamara, Coleen A.

AU - Husain, Mansoor

AU - Robbins, Clinton S.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - 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.

AB - 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.

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ER -

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

Abstract

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