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Article

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

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Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
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Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
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Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, 121552 Moscow, Russia
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Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, 119334 Moscow, Russia
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Kalen Biomedical, LLC, Montgomery Village, MD 20886, USA
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BIOSOFT.RU, LLC, 630090 Novosibirsk, Russia
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Institute of Computational Technologies, 630090 Novosibirsk, Russia
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geneXplain GmbH, 38302 Wolfenbüttel, Germany
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Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
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Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia
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Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei 10002, Taiwan
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Institute for Information Transmission Problems Russian Academy of Sciences, Bolshoy Karetny per. 19, build.1, 127051 Moscow, Russia
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Vavilov Institute of General Genetics Russian Academy of Sciences, Gubkina str. 3, 119333 Moscow, Russia
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Moscow Institute of physics and technology, 9 Institutskiy per., 141701 Dolgoprudny, Moscow Region, Russia
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Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia
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Department of Aging Research, Graduate school of Medicine, Chiba University, Chiba 263-8522, Japan
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Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
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Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2716; https://doi.org/10.3390/ijms21082716
Received: 16 March 2020 / Revised: 3 April 2020 / Accepted: 7 April 2020 / Published: 14 April 2020
(This article belongs to the Special Issue Immunoglobulins in Inflammation)
Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation. View Full-Text
Keywords: atherosclerosis; foam cells; gene knockdown; inflammatory molecules; latex beads; macrophages; modified low-density lipoprotein; phagocytosis; self-association; signaling pathways; transcriptome analysis atherosclerosis; foam cells; gene knockdown; inflammatory molecules; latex beads; macrophages; modified low-density lipoprotein; phagocytosis; self-association; signaling pathways; transcriptome analysis
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MDPI and ACS Style

Orekhov, A.N.; Sukhorukov, V.N.; Nikiforov, N.G.; Kubekina, M.V.; Sobenin, I.A.; Foxx, K.K.; Pintus, S.; Stegmaier, P.; Stelmashenko, D.; Kel, A.; Poznyak, A.V.; Wu, W.-K.; Kasianov, A.S.; Makeev, V.Y.; Manabe, I.; Oishi, Y. Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First? Int. J. Mol. Sci. 2020, 21, 2716. https://doi.org/10.3390/ijms21082716

AMA Style

Orekhov AN, Sukhorukov VN, Nikiforov NG, Kubekina MV, Sobenin IA, Foxx KK, Pintus S, Stegmaier P, Stelmashenko D, Kel A, Poznyak AV, Wu W-K, Kasianov AS, Makeev VY, Manabe I, Oishi Y. Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First? International Journal of Molecular Sciences. 2020; 21(8):2716. https://doi.org/10.3390/ijms21082716

Chicago/Turabian Style

Orekhov, Alexander N., Vasily N. Sukhorukov, Nikita G. Nikiforov, Marina V. Kubekina, Igor A. Sobenin, Kathy K. Foxx, Sergey Pintus, Philip Stegmaier, Daria Stelmashenko, Alexander Kel, Anastasia V. Poznyak, Wei-Kai Wu, Artem S. Kasianov, Vsevolod Y. Makeev, Ichiro Manabe, and Yumiko Oishi. 2020. "Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?" International Journal of Molecular Sciences 21, no. 8: 2716. https://doi.org/10.3390/ijms21082716

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