title: Phosphatidylserine liposomes mimic apoptotic cells to attenuate atherosclerosis by expanding polyreactive IgM producing B1a lymphocytes.
abstract: OBJECTIVE
  To investigate whether activation of atheroprotective peritoneal B1a cells by apoptotic cells or phosphatidylserine liposomes (PSLs) can enhance their protective actions during atherosclerosis development.
  
  
  RESULTS
  Male apolipoprotein E-knockout (ApoE-/-) mice were treated with apoptotic cells or PSLs at the beginning of 8-week high-fat diet. Intraperitoneally administered apoptotic cells attenuated atherosclerosis in hypercholesterolemic ApoE-/- mice by 53% and macrophage accumulation by 52%, effects mimicked by administering PSLs and abolished by B1a cell depletion by splenectomy. These effects were associated with reduced lesion CD4+ and CD8+ T cells, mRNAs of MCP-1, VCAM-1, TNF-α, IL-1β, IL-12, and IL-18 while anti-inflammatory TGF-β mRNA levels doubled. Apoptotic cells or PSLs increased B1a lymphocytes including TIM-1+ B1a cells in vivo and in vitro while other lymphocyte populations were unaffected. Total plasma IgM, anti-leucocyte, anti-CD3, anti-CD4, and anti-oxLDL IgM were elevated. IgM in atherosclerotic lesions was also elevated and this was associated with reduced lesion MDA-LDL (oxLDL), apoptotic cells and necrotic core size. These effects of activating B1a cells could be attributed to B1a-derived polyreactive IgM deposited in lesions that reduce inflammatory cytokines by lowering lesion ox-LDL via anti-oxLDL IgM, T-cells via anti-leucocyte, anti-CD3, and anti-CD4 IgM, apoptotic cells and necrotic core size via IgM binding to apoptotic cells and enhancing phagocytosis, which also elevates anti-inflammatory cytokines.
  
  
  CONCLUSIONS
  Targeting B1a cell activation by PSLs may be a potentially potent therapeutic strategy to attenuate atherosclerosis and reduce the incidence of atherosclerosis-dependent myocardial infarction and stroke.
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia.
authors: Hamid
authors: H
authors: Hosseini
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia.
authors: Yi
authors: Y
authors: Li
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia.
authors: Peter
authors: P
authors: Kanellakis
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia.
authors: Christopher
authors: C
authors: Tay
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia.
authors: Anh
authors: A
authors: Cao
authors: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia.
authors: Peter
authors: P
authors: Tipping
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
authors: Alex
authors: A
authors: Bobik
authors: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia.
authors: Ban-Hock
authors: BH
authors: Toh
authors: BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Vic 3004, Melbourne 6492, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, VIC, Australia tinsoe.kyaw@bakeridi.edu.au.
authors: Tin
authors: T
authors: Kyaw
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008081:Liposomes; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D018345:Mice, Knockout; D009336:Necrosis; D010587:Phagocytosis; D010641:Phenotype; D010718:Phosphatidylserines / Q000008:administration & dosage*; D013156:Splenectomy; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D007075:Immunoglobulin M; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D008081:Liposomes; D010718:Phosphatidylserines; C099252:oxidized low density lipoprotein
keywords: Apoptotic cells; Atherosclerosis; B1a cells; IgM; Phosphatidylserine liposomes