Perivascular Adipose Tissue Harbors Atheroprotective IgM-Producing B Cells.

Prasad Srikakulapu,M Beatriz S Lopes,Alexandra W Hickman,Melissa A Marshall,Angela M Taylor,Sam M Rosenfeld,Gorav Ailawadi,Chantel Mcskimming,Coleen A Mcnamara,Ileana S Mauldin,Aditi Upadhye

doi:10.3389/fphys.2017.00719

Prasad Srikakulapu, M Beatriz S Lopes + Show 9 more

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https://doi.org/10.3389/fphys.2017.00719

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Abstract

Adipose tissue surrounding major arteries (Perivascular adipose tissue or PVAT) has long been thought to exist to provide vessel support and insulation. Emerging evidence suggests that PVAT regulates artery physiology and pathology, such as, promoting atherosclerosis development through local production of inflammatory cytokines. Yet the immune subtypes in PVAT that regulate inflammation are poorly characterized. B cells have emerged as important immune cells in the regulation of visceral adipose tissue inflammation and atherosclerosis. B cell-mediated effects on atherosclerosis are subset-dependent with B-1 cells attenuating and B-2 cells aggravating atherosclerosis. While mechanisms whereby B-2 cells aggravate atherosclerosis are less clear, production of immunoglobulin type M (IgM) antibodies is thought to be a major mechanism whereby B-1 cells limit atherosclerosis development. B-1 cell-derived IgM to oxidation specific epitopes (OSE) on low density lipoproteins (LDL) blocks oxidized LDL-induced inflammatory cytokine production and foam cell formation. However, whether PVAT contains B-1 cells and whether atheroprotective IgM is produced in PVAT is unknown. Results of the present study provide clear evidence that the majority of B cells in and around the aorta are derived from PVAT. Interestingly, a large proportion of these B cells belong to the B-1 subset with the B-1/B-2 ratio being 10-fold higher in PVAT relative to spleen and bone marrow. Moreover, PVAT contains significantly greater numbers of IgM secreting cells than the aorta. ApoE−/− mice with B cell-specific knockout of the gene encoding the helix-loop-helix factor Id3, known to have attenuated diet-induced atherosclerosis, have increased numbers of B-1b cells and increased IgM secreting cells in PVAT relative to littermate controls. Immunostaining of PVAT on human coronary arteries identified fat associated lymphoid clusters (FALCs) harboring high numbers of B cells, and flow cytometry demonstrated the presence of T cells and B cells including B-1 cells. Taken together, these results provide evidence that murine and human PVAT harbor B-1 cells and suggest that local IgM production may serve to provide atheroprotection.

Highlights

Atherosclerosis, a chronic inflammatory disease of arteries, is the major underlying cause of cardiovascular disease (CVD)
We identified Inhibitor of differentiation3 (Id3), a basic helix-loop-helix protein that inhibits E-proteins binding to DNA to regulate transcription as an inhibitor of B-1 cell number and immunoglobulin type M (IgM) production in visceral adipose tissue (Harmon et al, 2016)
Flow cytometry revealed greater numbers of CD19+ B cells, CD5+ T cells and double negative cells (DN: CD19− CD5−) in the perivascular adipose tissue (PVAT) compared to the aorta (Figure 1B)

Summary

Introduction

Atherosclerosis, a chronic inflammatory disease of arteries, is the major underlying cause of cardiovascular disease (CVD). Atherosclerosis develops when low density lipoprotein (LDL) enters the artery wall, becomes oxidized. Products of oxidized lipids are highly reactive and modify self-molecules, thereby generating structural neo-epitopes that are recognized by receptors of the immune system, including scavenger receptors on macrophages leading to foam cell formation. These neo-epitopes are termed oxidation specific epitopes (OSEs) and represent a common set of epitopes present on various oxidatively modified self-proteins and lipids (Chou et al, 2008; Miller et al, 2011). Oxidized LDL (OxLDL) and foam cells promote inflammatory cytokine production and endothelial cell adhesion molecule expression, leading to recruitment of inflammatory cells such as, monocytes, T cells, natural killer cells, natural killer T cells, and dendritic cells into the intima, fueling lesion formation (Hansson and Hermansson, 2011; Wigren et al, 2012; Binder et al, 2016)

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