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Journal highlights December - novel advances in the research on inflammation in atherosclerosis

Thursday 21 December 2017   (0 Comments)
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Volume 267 Issue December 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

From the very beginning of atherosclerosis research, inflammation has been considered as a pivotal pathogenic process of atherosclerosis. The large evidence having accumulated over decades has culminated in the CANTOS trial, which showed that interference with inflammation by blockade of interleukin 1 beta signalling reduces cardiovascular event rates. This issue of Atherosclerosis contains several articles summarizing or reporting novel advances in the research on inflammation in atherosclerosis.

Issue highlights


    Highlighted articles

    NLRP3 inflammasome pathways in atherosclerosis

    Atherosclerosis is the major cause of death and disability worldwide. Atherosclerotic plaques are characterized by a chronic sterile inflammation in the large blood vessels, where lipid-derived and damage-associated molecular patterns play important roles in inciting immune responses. Following the initial demonstration that NLR family pyrin domain containing 3 (NLRP3) is important for atherogenesis, a substantial number of studies have emerged addressing the basic mechanisms of inflammasome activation and their relevance to atherosclerosis. Such studies have demonstrated that multiple players are involved in regulating NLRP3 inflammasome and that regulation of inflammasome affects atherosclerosis development. In this review, Baldrighi et al. discuss the basic cellular and molecular mechanisms of NLRP3 inflammasome activation, and the current findings and therapeutic strategies that target NLRP3 inflammasome activation during the development and progression of atherosclerosis

    Community-based statins and advanced carotid plaque: Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque

    Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoproteins, is associated with an approximate two-fold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the atheromatous plaque.

    Otsuka et al. collected carotid plaques from symptomatic and asymptomatic patients with or without documented statin history. In all cases, the primary stenosis was removed by endarterectomy. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index).

    Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets as well as Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2.

    Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity. Therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce inflammation and cell death in lesions, and thereby prevent necrotic core expansion and lesion progression.

    Activation-induced FOXP3 isoform profile in peripheral CD4+ T cells is associated with coronary artery disease

    The transcription factor FOXP3 is crucial for the development and maintenance of immunosuppressive regulatory T (Treg) cells. Impaired Treg cell function has been attributed to chronic inflammatory diseases, such as cardiovascular disease (CVD). Reduced Treg cell function has been associated with coronary artery disease (CAD), the most common form of CVD. However, contradicting results are reported for the FOXP3+ Treg cell population in peripheral blood mononuclear cells (PBMCs) obtained from CVD patients, indicating that detection of FOXP3 in human specimen might be hampered by post-transcriptional modifications. Alternative splicing of FOXP3 in CAD has not been investigated so far.

    Lundberg et al. quantified FOXP3 splice variants and IL17A transcripts in peripheral blood mononuclear cells from stable CAD patients and healthy controls, and FOXP3 isoform expression in response to T cell receptor (TCR) stimulation or low-density lipoprotein (LDL) was analyzed by flow cytometry.

    Compared to healthy controls, CAD patients expressed significantly more FOXP3 transcripts including exon 2, while alternative splicing of exon 7 in correlation with IL17A expression, was reduced. TCR stimulation and exposure to LDL decreased alternative splicing of FOXP3 in CD4+ T cells in vitro.

    These results demonstrate that blood mononuclear cells in stable CAD patients express a ratio of FOXP3 isoforms that is characteristic for activated CD4+ T cells.

    Increased serum TREM-1 level is associated with in-stent restenosis, and activation of TREM-1 promotes inflammation, proliferation and migration in vascular smooth muscle cells

    In-stent restenosis (ISR) remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents, and the mechanism of ISR has not been fully clarified. Triggering receptor expressed on myeloid cells (TREM)-1 is a critical regulator of acute inflammatory responses through synergizing with Toll like receptors in infectious and non-infectious diseases. In the present study, Wang et al. investigated the potential association of serum soluble TREM-1 (sTREM-1) levels with the incidence of ISR. The role of TREM-1 was evaluated in cultured vascular smooth muscle cells (VSMCs).

    130 out of 1683 patients, undergoing coronary intervention and follow-up coronary angiography after approximately one year, were diagnosed with ISR, and 150 gender- and age-matched patients with no ISR were randomly included as controls. Levels of sTREM-1 were determined by ELISA. The role of TREM-1 signaling in the activation of VSMCs was tested.

    Serum sTREM-1 concentrations were significantly elevated in patients with ISR compared to those without. Multivariable logistic regression analysis showed that sTREM-1, besides conventional factors, was independently associated with the incidence of ISR. Evident expression of TREM-1 in VSMCs was detected in the neointimal and medial layers of stenotic lesions of mouse carotid ligation models. In cultured VSMCs, expression of TREM-1 was significantly induced upon exposure to lipopolysaccharide. Blocking TREM-1 with a synthetic inhibitory peptide (LP17) dramatically inhibited cellular inflammation, proliferation and migration in VSMCs while TREM-1-activating antibody promoted these processes.

    These data suggest that TREM-1 is a predictive biomarker of ISR and an important mediator of cellular inflammation, migration, and proliferation in VSMCs. Pharmacological inhibition of TREM-1 may serve as a promising approach to attenuate progression of ISR.

    Ex vivo culture of human atherosclerotic plaques: A model to study immune cells in atherogenesis

    The mechanisms driving atherosclerotic plaque progression and destabilization in humans remain largely unknown. Laboratory models are needed to study these mechanisms under controlled conditions. Lebedeva et al. aimed to establish a novel ex vivo model of human atherosclerotic plaques that preserves the main cell types in plaques and the extracellular components in their native cytoarchitecture.

    Atherosclerotic plaques from carotid arteries of 28 patients undergoing carotid endarterectomy were dissected and cultured. At various time points, samples were collected for histological analysis. After enzymatic digestion, single cells were analysed by flow cytometry and tissue cytokine production was evaluated.

    The plaque dissection protocol was optimized by cutting plaques into circular segments cultured on collagen rafts at the medium–air interface, thus keeping them well oxygenated. With this technique, the relative presence of T and B lymphocytes did not change significantly during culture, and the sizes of lymphocyte subsets remained stable after day 4 of culture. The authors showed that the major plaque cell types, i.e. macrophages, smooth muscle cells, and fibroblasts with collagen fibers, T and B lymphocyte subsets and CD16 natural killer cells, remained largely preserved for the entire culture period (19 days of culture), and the plaque tissue continued to release cytokines and chemokines during culture.

    This new model of ex vivo human atherosclerotic plaques, which preserves the main subsets of immune cells in their tissue cytoarchitecture, may be used to investigate complex immunological aspects of atherogenesis, in particular, the functions of immune cells under controlled laboratory conditions.

    Electronegative L5-LDL induces the production of G-CSF and GM-CSF in human macrophages through LOX-1 involving NF-κB and ERK2 activation

    Circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are associated with the severity of acute myocardial infarction (AMI). However, the reasons for increased in G-CSF and GM-CSF is unclear. Yang et al. recently reported a substantial increase in L5-low-density lipoprotein (L5-LDL), a naturally occurring, mildly oxidized LDL, in patients with ST-segment elevation myocardial infarction (STEMI) and showed that L5-LDL induced nuclear factor (NF)-κB and inflammasome activation and subsequent production of interleukin (IL)-1β in macrophages. Since NF-κB has been shown to regulate G-CSF and GM-CSF, in this study, the authors investigated whether L5-LDL can induce G-CSF and GM-CSF production in human macrophages.

    L1-LDL and L5-LDL were isolated by anion-exchange chromatography from AMI plasma. Human macrophages, derived from a human monocytic leukemia cell line (THP-1), and peripheral blood mononuclear cells were treated with L1-LDL, L5-LDL, or copper-oxidized LDL (Cu-oxLDL) and G-CSF and GM-CSF protein levels in the medium were determined. In addition, the effects of L5-LDL on G-CSF and GM-CSF production were tested in THP-1 macrophages with knockdowns of lectin-type oxidized LDL receptor-1 (LOX-1), CD36, extracellular signal-regulated kinase (ERK) 1, or ERK2.

    L5-LDL but not L1-LDL or Cu-oxLDL significantly induced production of G-CSF and GM-CSF in macrophages. In vitro oxidation of L1-LDL and L5-LDL altered their ability to induce G-CSF and GM-CSF, suggesting that the degree of oxidation is critical for G-CSF and GM-CSF production. Knockdown and antibody neutralization experiments suggested that these effects were caused by LOX-1. NF-κB and ERK1/2 inhibition resulted in marked reductions of L5-LDL-induced G-CSF and GM-CSF production. Moreover, knockdown of ERK2, but not ERK1, hindered L5-LDL-induced G-CSF and GM-CSF production.

    The results indicate that L5-LDL induced G-CSF and GM-CSF production in human macrophages through LOX-1, ERK2, and NF-κB dependent pathways.

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