학술논문
c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells
Document Type
article
Author
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
Source
Cell Reports, Vol 27, Iss 8, Pp 2304-2312.e6 (2019)
Subject
Language
English
ISSN
2211-1247
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.