Commensal Microbe-specific Activation of B2 Cell Subsets Contributes to Atherosclerosis Development Independently of Lipid Metabolism.
The relation between B2 cells and commensal microbes during atherosclerosis remains largely unexplored. Here we show that under hyperlipidemic conditions intestinal microbiota resulted in recruitment and ectopic activation of B2 cells in perivascular adipose tissue, followed by an increase in circulating IgG, promoting disease development. In contrast, disruption of the intestinal microbiota by a broad-spectrum antibiotic cocktail (AVNM) led to the attenuation of atherosclerosis by suppressing B2 cells, despite the persistence of serum lipid abnormalities. Furthermore, pharmacological depletion of B2 cells with an anti-B2-cell surface CD23 antibody also attenuated commensal microbe-induced atherosclerosis. Moreover, expression analysis of TLR-signaling-related genes in the activated B2 cell subsets, assessed using the Toll-Like Receptor Signaling Pathway RT2 Profiler PCR Array, confirmed activation of the B2-cell autoantibody-production axis, which was associated with an increased capacity of B2 cells to bind to intestinal microbiota. Together, our findings reveal the critical role of commensal microbe-specific activation of B2 cells in the development of atherogenesis through lipid metabolism-independent mechanisms.
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Lin
L
Chen
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan. Electronic address: tommmish@hotmail.com.
Tomoaki
T
Ishigami
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Rie
R
Nakashima-Sasaki
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Tabito
T
Kino
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Hiroshi
H
Doi
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Shintaro
S
Minegishi
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
Satoshi
S
Umemura
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000276:immunology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D058226:Plaque, Atherosclerotic / Q000473:pathology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D055114:X-Ray Microtomography
D000900:Anti-Bacterial Agents; D016207:Cytokines; D018836:Inflammation Mediators; D051193:Toll-Like Receptors
Atherosclerosis; B2 cell; Inflammation; Intestinal microbiota; TLR signaling