Toll‐Like Receptor (TLR)4 and MyD88 are Essential for Atheroprotection by Peritoneal B1a B Cells
| Autor: | Yi Li, Peter Kanellakis, Anh Cao, Peter G. Tipping, Ban-Hock Toh, Tin Kyaw, Alex Bobik, Hamid Hosseini, Edgar Liu, Christopher Tay, Karlheinz Peter |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Mice Knockout ApoE medicine.medical_treatment Interleukin-1beta Vascular Medicine Mice 0302 clinical medicine Vascular Disease cytokine Medicine Toll‐like receptor 4/MyD88 Original Research Mice Knockout B-Lymphocytes Toll-like receptor biology Interleukin-18 medicine.anatomical_structure Cytokine Tumor necrosis factor alpha Peritoneum medicine.symptom Cardiology and Cardiovascular Medicine IgM B-Lymphocyte Subsets Inflammation Diet High-Fat Real-Time Polymerase Chain Reaction Proinflammatory cytokine Transforming Growth Factor beta1 03 medical and health sciences Phagocytosis Vascular Biology Animals B cell Tumor Necrosis Factor-alpha business.industry Transforming growth factor beta Atherosclerosis Toll-Like Receptor 2 Toll-Like Receptor 4 B1a cells TLR2 030104 developmental biology Immunoglobulin M inflammation Toll-Like Receptor 9 Myeloid Differentiation Factor 88 Immunology biology.protein Cancer research business 030215 immunology |
| Zdroj: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| ISSN: | 2047-9980 |
| DOI: | 10.1161/jaha.115.002947 |
| Popis: | Background We previously identified peritoneal B1a cells that secrete natural IgM as a key atheroprotective B cell subset. However, the molecules that activate atheroprotective B1a cells are unknown. Here, we investigated whether Toll‐like receptors (TLRs) TLR 2, TLR 4, and TLR 9 expressed by B1a cells are required for IgM‐mediated atheroprotection. Methods and Results We adoptively transferred B1a cells from wild‐type mice or from mice deficient in TLR 2, TLR 4, TLR 9, or myeloid differentiation primary response 88 (MyD88) into ApoE −/− mice depleted of peritoneal B1a cells by splenectomy and fed a high‐fat diet for 8 weeks. Elevations in plasma total, anti‐oxLDL (oxidized low‐density lipoprotein), anti‐leukocyte, anti‐ CD 3, anti‐ CD 8, and anti‐ CD 4 IgMs in atherosclerotic mice required B1a cells expressing TLR 4 and MyD88, indicating a critical role for TLR 4‐MyD88 signaling for IgM secretion. Suppression of atherosclerosis was also critically dependent on B1a cells expressing TLR 4‐MyD88. Atherosclerosis suppression was associated not only with reductions in lesion apoptotic cells, necrotic cores, and ox LDL , but also with reduced lesion CD 4 + and CD 8 + T cells. Transforming growth factor beta 1 ( TGF ‐β1) expression, including macrophages expressing TGF ‐β1, was increased, consistent with increased IgM‐mediated phagocytosis of apoptotic cells by macrophages. Reductions in lesion inflammatory cytokines tumor necrosis factor alpha ( TNF ‐α), interleukin ( IL) 1β, and IL ‐18 were consistent with augmented TGF ‐β1 expression. Conclusions TLR 4‐MyD88 expression on B1a cells is critical for their IgM‐dependent atheroprotection that not only reduced lesion apoptotic cells and necrotic cores, but also decreased CD 4 and CD 8 T‐cell infiltrates and augmented TGF ‐β1 expression accompanied by reduced lesion inflammatory cytokines TNF ‐α, IL ‐1β, and IL ‐18. |
| Databáze: | OpenAIRE |
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