IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

Abstract

IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophagerich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na + /H + exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.

Is Atherosclerosis an Allergic Disease?

“…Likely, the proatherogenic activity of IgE in humans is more complex. In contrast to the data described by Wang et al, 10 IgE binding to Fc⑀R1␣ was previously reported to actually promote the survival of human monocytes, 16 and in another report, it was reported to induce proinflammatory effects through the low affinity IgE receptor (CD23), including the release of interleukin-6 and thromboxane B 2 in human B lymphocytes. 17 Nevertheless, these studies suggest novel ways by which IgE may contribute to inflammation and destabilization of the advanced plaque and thus could be relevant to clinical disease.…”

“…10 It is not clear at what time in relation to acute events these levels were measured, nor were control patients with other acute illness sampled. Because the prevalence of known CVD risk factors was very high in the CVD patients studied, it is not possible to determine whether the elevated IgE levels are disease associated or possibly disease causing.…”

“…The report by Wang et al 10 and other reports describing the potential importance of mast cells to CVD have provided a compelling case to study the role of IgE in inflammatory conditions such as atherosclerosis. It adds to the growing evidence of the importance of immune function in atherogenesis and in particular of the role that immunoglobulins play, both through antigen-specific interactions and antigenindependent regulatory roles.…”

Interruption of the OX40–OX40 Ligand Pathway in LDL Receptor–Deficient Mice Causes Regression of Atherosclerosis

“…Furthermore, switching mice to a low-fat diet does not affect mast cell numbers but reduces mast cell activation, thereby possibly reducing the recruitment of new immune cells to the site of inflammation. Additionally, enhanced IgE levels were observed in patients with unstable angina pectoris and in dyslipidemia (47,48), and recently Wang et al (49) showed that IgE promotes atherosclerosis in ApoE 2/2 mice. In line with these findings, we suggest that IgE may play an important role in atherosclerosis and show that modulation of the OX40-OX40L pathway reduces IgE levels and thereby contributes to lesion regression.…”

Adaptive Response of T and B Cells in Atherosclerosis

“…Notably, Fc epsilon receptor I (IgE receptor) deficiency reduces atherosclerosis in Apoe −/− mice. 44 Th2 cytokines are known modulators of eosinophil and mast cell responses, both cells that could as well influence disease. 45,46 Th17 cells have been implicated in autoimmune diseases, such as multiple sclerosis, and have been recently raising attention in atherosclerosis.…”