title: Toll-Like Receptor (TLR)4 and MyD88 are Essential for Atheroprotection by Peritoneal B1a B Cells.
abstract: 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) TLR2, TLR4, and TLR9 expressed by B1a cells are required for IgM-mediated atheroprotection.
  
  
  
  We adoptively transferred B1a cells from wild-type mice or from mice deficient in TLR2, TLR4, TLR9, 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-CD3, anti-CD8, and anti-CD4 IgMs in atherosclerotic mice required B1a cells expressing TLR4 and MyD88, indicating a critical role for TLR4-MyD88 signaling for IgM secretion. Suppression of atherosclerosis was also critically dependent on B1a cells expressing TLR4-MyD88. Atherosclerosis suppression was associated not only with reductions in lesion apoptotic cells, necrotic cores, and oxLDL, but also with reduced lesion CD4+and CD8+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.
  
  
  
  TLR4-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 CD4 and CD8 T-cell infiltrates and augmented TGF-β1 expression accompanied by reduced lesion inflammatory cytokines TNF-α, IL-1β, and IL-18.
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.|Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Hamid
authors.initials: H
authors.lastname: Hosseini
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.|Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.|Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tay
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Anh
authors.initials: A
authors.lastname: Cao
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Edgar
authors.initials: E
authors.lastname: Liu
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.|Department of Immunology, Faculty of Medicine, Nursing and Health Sciences Monash University, Clayton, Australia.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Tipping
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Ban-Hock
authors.initials: BH
authors.lastname: Toh
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia.|Department of Immunology, Faculty of Medicine, Nursing and Health Sciences Monash University, Clayton, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
authors.affiliation: BakerIDI heart and Diabetes Institute, Melbourne, Australia tinsoe.kyaw@bakeridi.edu.au.|Department of Medicine, Centre for Inflammatory Diseases, Southern Clinical School, Clayton, Australia.
authors.forename: Tin
authors.initials: T
authors.lastname: Kyaw
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D059305:Diet, High-Fat; D007075:Immunoglobulin M / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074085:Mice, Knockout, ApoE; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D010537:Peritoneum / Q000166:cytology / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C587672:IL1B protein, mouse; D007075:Immunoglobulin M; D020382:Interleukin-18; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C508961:Tgfb1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha
keywords: B1a cells; IgM; Toll‐like receptor 4/MyD88; atherosclerosis; cytokine; inflammation