Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques

George, Jacob; Schwartzenberg, Shmuel; Medvedovsky, Diego; Jonas, Michael; Charach, Gideon; Afek, Arnon; Shamiss, Ari

doi:10.1016/j.atherosclerosis.2012.03.016

Cited by 97 publications

(67 citation statements)

References 26 publications

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“…CD4 + Foxp3 + T regs contribute to atheroprotection 35–36 and are linked to plaque stability in humans. 37 In addition, the percentage of antigen‐presenting cells, that is, myeloid dendritic cells (mDCs; B220 − /CD3 − /CD11b + /CD11c + ) and monocyte/macrophages (B220 − /CD3 − /CD11b + /CD11c − /SSC low ), were 2‐ to 3‐fold higher in DKO lymph nodes ( P <0.05; Table 3). MHCII expression was higher on DKO versus Apoe −/− mDCs (mean fluorescence intensity: 4947±677 vs. 2339±513, respectively, n=3; P <0.05), consistent with DC maturation 38 and an up‐regulation that often accompanies T naive →T reg conversion.…”

Section: Resultsmentioning

confidence: 99%

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Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques

Harmon

Fronhofer

Keller

et al. 2014

JAHA

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BackgroundStroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcγR) expression than their stable counterparts, how FcγR expression impacts plaque histology is unknown. We investigated the role of FcγRIIb in carotid plaque development and stability in apolipoprotein (Apo)e−/− and Apoe−/−FcγRIIb−/− double knockout (DKO) animals.Methods and ResultsPlaques were induced by implantation of a shear stress‐modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe−/− mice were foam‐cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg‐1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)‐10, immune complexes, and regulatory T cells (Tregs) and lower IL‐12, IL‐1β, and tumor necrosis factor alpha (TNF‐α) in DKO mice. Similarly, in vitro stimulation produced higher IL‐10 and Arg‐1 and lower iNOS, IL‐1β, and TNF‐α in DKO versus Apoe−/− macrophages. These results define a systemic anti‐inflammatory phenotype.ConclusionsWe hypothesized that removal of FcγRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcγRIIb on a congenic C57BL/6 background induces an anti‐inflammatory Treg/M2 polarization that is atheroprotective.

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Section: Resultsmentioning

confidence: 99%

“…That the model has translational potential is apparent from studies reporting that humans that have elevated levels of IL‐10 and T regs develop less‐vulnerable plaques. 37 …”

Section: Discussionmentioning

confidence: 99%

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques

Harmon

Fronhofer

Keller

et al. 2014

JAHA

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“…Finally, in humans, George et al (2012) found that serum IL-10 levels were lower in patients with clinically overt coronary artery disease (e.g., a previous myocardial infarction) as compared to "stable" patients with disease burden but without clinical events (George et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages

Salari

Seibert

Chen

et al. 2013

Cell Stress and Chaperones

114

134

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Heat shock protein 27 (HSP27) shows attenuated expression in human coronary arteries as the extent of atherosclerosis progresses. In mice, overexpression of HSP27 reduces atherogenesis, yet the precise mechanism (s) are incompletely understood. Inflammation plays a central role in atherogenesis, and of particular interest is the balance of pro-and anti-inflammatory factors produced by macrophages. As nuclear factor-kappa B (NF-κB) is a key immune signaling modulator in atherogenesis, and macrophages are known to secrete HSP27, we sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling in macrophages. Treatment of THP-1 macrophages with rHSP27 resulted in the degradation of an inhibitor of NF-κB, IκBα, nuclear translocation of the NF-κB p65 subunit, and increased NF-κB transcriptional activity. Treatment of THP-1 macrophages with rHSP27 yielded increased expression of a variety of genes, including the pro-inflammatory factors, IL-1β, and TNF-α. However, rHSP27 also increased the expression of the anti-inflammatory factors IL-10 and GM-CSF both at the mRNA and protein levels. Our study suggests that in macrophages, activation of NF-κB signaling by rHSP27 is associated with upregulated expression and secretion of key pro-and anti-inflammatory cytokines. Moreover, we surmise that it is the balance in expression of these mediators and antagonists of inflammation, and hence atherogenesis, that yields a favorable net effect of HSP27 on the vessel wall.

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“…Tregs serve to maintain immunological tolerance and suppress effector T cell responses (187). The atheroprotective effect of Tregs on atherosclerosis has been reported in both a mouse model and a human study (188,189).…”

Section: Inflammationmentioning

confidence: 99%

Stabilization of high-risk plaques

Takata¹,

Imaizumi²,

Zhang³

et al. 2016

Cardiovasc. Diagn. Ther.

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Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques

Cited by 97 publications

References 26 publications

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages

Stabilization of high-risk plaques

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Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques

Cited by 97 publications

References 26 publications

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe −/− FcγRIIb −/− Mice Develop Fibrous Carotid Plaques

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe −/− FcγRIIb −/− Mice Develop Fibrous Carotid Plaques

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages

Stabilization of high-risk plaques

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Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques

Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe ^−/− FcγRIIb ^−/− Mice Develop Fibrous Carotid Plaques