Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis

Subramanian, Manikandan; Thorp, Edward B.; Tabas, Ira

doi:10.1161/circresaha.116.304794

Cited by 75 publications

(43 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In vitro stimulation of PBMCs gives the opportunity to study the interplay between different immune cells and 24,25 Recently, however, IL-23 has also been shown to have important proatherogenic effects on macrophages, independently of IL-17. 26 In our study, IL-23 significantly increased TNF release in patient monocytes, and we also found colocalization of IL-23/IL-23R and macrophages within the atherosclerotic lesion, supporting an interplay between monocytes/macrophages and IL-23 in atherosclerotic disease. In contrast to the increased expression of IL-23/IL-23R in carotid plaques, this was not seen in PBMCs from these patients, suggesting that the upregulation of IL-23/IL-23R in PBMC-related cells, such as macrophages, within the atherosclerotic lesion reflects processes within the plaque.…”

Section: Discussionsupporting

confidence: 82%

Interleukin 23 Levels Are Increased in Carotid Atherosclerosis

Abbas

Gregersen

Holm

et al. 2015

Stroke

View full text Add to dashboard Cite

793S troke is one of the major causes of death and disability worldwide. Approximately 85% of all strokes are ischemic, and 20% to 30% of these are caused by carotid atherosclerosis. Moderate-to high-grade carotid artery stenosis can be detected in 1% to 3% of adults, and the incidence increases with age. [1][2][3] Along with the degree of stenosis, inflammation and plaque composition are important in predicting the risk of clinical symptoms. 4 The atherosclerotic plaque is composed of infiltrating inflammatory cells (eg, monocytes/macrophages, T cells, and dendritic cells [DCs]), smooth muscle cells, and lipids. Plaques prone to rupture have thin fibrous caps and high-grade inflammation. The balance between pro-and anti-inflammatory mediators is therefore of major importance for the fate of the plaque and for the occurrence of adverse events. 5,6Background and Purpose-Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis. Methods-Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells. Results-Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8-10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) 14-16 Thus, patients with peripheral arterial disease have raised serum levels of IL-23, and increased IL-23 expression is seen in human carotid lesions.14,16 Zhang et al 17 showed that carriers of a polymorphism in the IL-23R gene, which also gave increased expression of IL-23R in peripheral blood mononuclear cells (PBMCs), had increased risk of coronary artery disease. However, decreased IL-23 in PBMCs from patients with coronary artery disease has also been reported. 18 In a mouse model of ischemic stroke, IL-23 levels were upregulated in both the circulation and in the brain. 15 However, the role for IL-23 in atherosclerosis is still unclear.In this study, we examined the expression of IL-23 in patients with carotid atherosclerosis both systemically and within the atherosclerotic plaque as well as its relation to adverse events during follow-up. We also examined the effect of IL-23 in PBMCs and monocytes from patients with carotid atherosclerosis and healthy controls. Mat...

show abstract

Section: Discussionsupporting

confidence: 82%

Interleukin 23 Levels Are Increased in Carotid Atherosclerosis

Abbas

Gregersen

Holm

et al. 2015

Stroke

View full text Add to dashboard Cite

show abstract

“…A recent study has demonstrated that GM-CSF functions as a growth factor and increases macrophage apoptosis in advanced lesions. 22 These effects are mediated by IL-23, another cytokine that we detected after TLR7 activation. Several prominent pro-inflammatory cytokines were unaffected by the TLR7 ligand in the plaques, including IFNc and IL-6.…”

Section: Discussionmentioning

confidence: 77%

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

et al. 2017

View full text Add to dashboard Cite

“…68 On the one hand, there is evidence that increased apoptosis of macrophages in advanced lesions, in which the clearance of apoptotic cells is impaired, 69 leads to enhanced lesion progression, expansion of the necrotic core, and increased risk of plaque rupture. Under these conditions, macrophage apoptosis can be enhanced by, for example, elevated endoplasmic reticulum stress, 70 granulocyte macrophage colony-stimulating factor-induced IL-23 production, 71 or excessive accumulation of oxysterols. 72 Especially relevant for the present study, PLCβ3 deletion results in a reduction in atherosclerotic lesions with increased macrophage apoptosis and reduced Bcl-XL expression.…”

Section: Discussionmentioning

confidence: 99%

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

Wang¹,

Pan²,

Wang³

et al. 2016

Circulation Research

View full text Add to dashboard Cite

Rationale: Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized low-density lipoprotein, exert cytotoxic effects on macrophages. Objective: To determine whether oxysterol-binding protein–related protein 4 L (ORP4L), an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis. Methods and Results: By hiring cell biological approaches and ORP4L − /− mice, we show that ORP4L coexpresses with and forms a complex with Gα q/11 and phospholipase C (PLC)-β3 in macrophages. ORP4L facilitates G-protein–coupled ligand-induced PLCβ3 activation, IP 3 production, and Ca 2+ release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains antiapoptotic Bcl-XL expression through Ca 2+ -mediated c-AMP responsive element binding protein transcriptional regulation and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gα q/11 /PLCβ3 complexes, resulting in reduced PLCβ3 activity, IP 3 production, and Ca 2+ release, as well as decreased Bcl-XL expression and increased apoptosis. Overexpression of ORP4L counteracts these oxysterol-induced defects. Mice lacking ORP4L exhibit increased apoptosis of macrophages in atherosclerotic lesions and a reduced lesion size. Conclusions: ORP4L is crucial for macrophage survival. It counteracts the cytotoxicity of oxysterols/oxidized low-density lipoprotein to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.

show abstract

Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis

Cited by 75 publications

References 65 publications

Interleukin 23 Levels Are Increased in Carotid Atherosclerosis

Interleukin 23 Levels Are Increased in Carotid Atherosclerosis

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

Contact Info

Product

Resources

About