IgE Contributes to Atherosclerosis and Obesity by Affecting Macrophage Polarization, Macrophage Protein Network, and Foam Cell Formation

Abstract

Objective: By binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe −/− mice and IgE-deficient Ige −/− mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe −/− Ige −/− mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency. Conclusions: IgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.

Factors Influencing Total Serum IgE in Adults: The Role of Obesity and Related Metabolic Disorders

“…Along these lines, increased IgE and subsequent mast cell activation have been found related to ischaemic heart disease [41]. Moreover, IgE may contribute to obesity and atherosclerosis in mice [42]. Further studies would be required to elucidate the mechanisms of elevation of total serum IgE in these metabolic disorders.…”

Abdominal Aortic Aneurysm: Roles of Inflammatory Cells

“…Besides, some of the immunoglobulin subtypes can interact with other immune cells. For instance, IgE can affect macrophage polarization and induce mast cell activated to synthesize various elastases ( 109 , 110 ). These dramatically increasing evidences indicate that B cell may be an ideal target to treat AAA patients, and subsequent experiments confirmed this hypothesis.…”

Functional Role of B Cells in Atherosclerosis

“…As FcεR1 and TLR4 interactions induce MΦ activation, FcεR1 deficiency attenuates MΦ signal transduction, inflammatory gene expression, apoptosis, and diminishes atherosclerosis [ 134 ]. Follow up studies directly tested a role of IgE in vascular cells using IgE-deficient ( Ige −/− ) Apoe −/− mice [ 135 ]. Ige −/− Apoe −/− mice demonstrated attenuated plaque burden, which was accompanied by a reduction in M1 MΦs, smooth muscle cells, and microvessels [ 135 ].…”

“…Follow up studies directly tested a role of IgE in vascular cells using IgE-deficient ( Ige −/− ) Apoe −/− mice [ 135 ]. Ige −/− Apoe −/− mice demonstrated attenuated plaque burden, which was accompanied by a reduction in M1 MΦs, smooth muscle cells, and microvessels [ 135 ]. Intriguingly, IgE also reduced MΦ-sterol-responsive network gene expression and promoted MΦ cholesteryl ester intracellular accumulation and foam cell formation and supported the development of obesity and diabetes mellitus, linking the development of atherosclerosis to metabolic diseases [ 135 ].…”