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Toll-Like Receptor (TLR)4 and MyD88 are Essential for Atheroprotection by Peritoneal B1a B Cells.

Abstract：

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) TLR2, TLR4, and TLR9 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 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. CONCLUSIONS: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.

journal_name

J Am Heart Assoc

journal_title

Journal of the American Heart Association

authors

Hosseini H,Li Y,Kanellakis P,Tay C,Cao A,Liu E,Peter K,Tipping P,Toh BH,Bobik A,Kyaw T

doi

10.1161/JAHA.115.002947

subject

Has Abstract

pub_date

2016-11-14 00:00:00

issue

issn

2047-9980

pii

JAHA.115.002947

journal_volume

pub_type

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Toll-Like Receptor (TLR)4 and MyD88 are Essential for Atheroprotection by Peritoneal B1a B Cells.