Phosphatidylserine liposomes mimic apoptotic cells to attenuate atherosclerosis by expanding polyreactive IgM producing B1a lymphocytes

Hamid Hosseini, Yi Li, Peter Kanellakis, Christopher Tay, Anh Cao, Peter George Tipping, Alexander Bobik, Ban-Hock Toh, Tin Soe Kyaw

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46 Citations (Scopus)

Abstract

AIMS: To investigate whether activation of atheroprotective peritoneal B1a cells by apoptotic cells or phosphatidylserine liposomes (PSLs) can enhance their protective actions during atherosclerosis development. METHODS AND 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-alpha, IL-1beta, IL-12, and IL-18 while anti-inflammatory TGF-beta 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. CONCLUSION: 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.
Original languageEnglish
Pages (from-to)443 - 452
Number of pages10
JournalCardiovascular Research
Volume106
Issue number3
DOIs
Publication statusPublished - 2015

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