Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages

October 29, 2018

One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion. Such changes of phenotype in comparison to normal macrophages should be based on changes in gene expression patterns of these cells. The study of foam cell formation is of key importance to our understanding of atherosclerosis pathogenesis and for the development of novel diagnostic and therapeutic tools. However, little is known so far on gene expression changes that take place during conversion of macrophages to foam cells.

Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Among the up-regulated genes were scavenger receptors SCA and CD36, nuclear receptors PPARγ, LXRα and RXRγ, and cholesterol efflux protein ABCA1. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities, such as IL1-RA, DSCR1, annexin 1, and the Burton's tyrosine kinase repressor SH3 protein, and down-regulation of a number of pro-inflammatory genes, including leukotriene A4 hydrolase, cathepsin G, elastase 2, RNase A family 2 and 3 proteins, cytochromeb-245, and CD64. However, modern powerful tools, such as transcriptome analysis, may provide more detailed data on change of gene expression patterns during atherosclerotic plaque development and reveal causative relationships between gene expression patterns and pathologic phenotypic alterations.

We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes. This strategy has three major steps: (1) analysis of promoters and enhancers of identified differentially expressed genes to identify transcription factors involved in the process under study; (2) reconstruction of signaling pathways that activate these transcription factors; and (3) identification of master-regulators of these pathways.

In this study, we used human monocyte-derived macrophages treated with different lipoprotein-containing samples : high-density lipoprotein (HDL), native LDL, which does not induce cholesterol accumulation in cultured cells, and 3 types of modified atherogenic LDL (oxidized LDL, acetylated LDL and desialylated LDL). In this experiment, low concentrations of native LDL and HDL did not increase the total or esterified cholesterol content in cultured macrophages. After incubation with the substances, mRNA was isolated from the cells and analysed using high-throughput sequencing on HiSeq 1500.

In this study, we discovered 27 transcription factors, including c-Ets, GR-alpha, BRCA1, E2F-1, E2F-6 and EGR-1, that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. The most reliable of identified master-regulators were IL7R, TIGIT, CXCL8, F2RL1, EIF2AK3, IL7, TSPYL2, ANXA1, DUSP1 and IL15. In the Discussion section of our paper, we give more detail on each of these master-regulators. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.
For more information, please visit:

Alexander N. Orekhov1,2*, Yumiko Oishi 3, Nikita G. Nikiforov1,4, Andrey V. Zhelankin5, Larisa Dubrovsky12, Igor A. Sobenin4, Alexander Kel6,7,8, Daria Stelmashenko6,7,8, Vsevolod J. Makeev9, Kathy Foxx10, Xueting Jin11, Howard S. Kruth11, Michael Bukrinsky12 *Corresponding author:

Alexander N. Orekhov
+7 903 169 08 66
Laboratory of Angiopathology
Institute of General Pathology and Pathophysiology
Moscow 125315, Russia

Bentham Science Publishers

Related Immune Response Articles from Brightsurf:

Boosting chickens' own immune response could curb disease
Broiler chicken producers the world over are all too familiar with coccidiosis, a parasite-borne intestinal disease that stalls growth and winnows flocks.

Cells sacrifice themselves to boost immune response to viruses
Whether flu or coronavirus, it can take several days for the body to ramp up an effective response to a viral infection.

Children's immune response more effective against COVID-19
Children and adults exhibit distinct immune system responses to infection by the virus that causes COVID-19, a finding that helps explain why COVID-19 outcomes tend to be much worse in adults, researchers from Yale and Albert Einstein College of Medicine report Sept.

Which immune response could cause a vaccine against COVID-19?
Immune reactions caused by vaccination can help protect the organism, or sometimes may aggravate the condition.

Obesity may alter immune system response to COVID-19
Obesity may cause a hyperactive immune system response to COVID-19 infection that makes it difficult to fight off the virus, according to a new manuscript published in the Endocrine Society's journal, Endocrinology.

Immune response to Sars-Cov-2 following organ transplantation
Even patients with suppressed immune systems can achieve a strong immune response to Sars-Cov-2.

'Relaxed' T cells critical to immune response
Rice University researchers model the role of relaxation time as T cells bind to invaders or imposters, and how their ability to differentiate between the two triggers the body's immune system.

A novel mechanism that triggers a cellular immune response
Researchers at Baylor College of Medicine present comprehensive evidence that supports a novel trigger for a cell-mediated response and propose a mechanism for its action.

Platelets exacerbate immune response
Platelets not only play a key role in blood clotting, but can also significantly intensify inflammatory processes.

How to boost immune response to vaccines in older people
Identifying interventions that improve vaccine efficacy in older persons is vital to deliver healthy ageing for an ageing population.

Read More: Immune Response News and Immune Response Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to