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Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, 121552 Moscow, Russia
Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, 119334 Moscow, Russia
Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei 10002, Taiwan
Kalen Biomedical, LLC, Montgomery Village, MD 20886, USA
BIOSOFT.RU, LLC, 630090 Novosibirsk, Russia
Institute of Computational Technologies, 630090 Novosibirsk, Russia
geneXplain GmbH, 38302 Wolfenbüttel, Germany
Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
N. N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoye sh., 115478 Moscow, Russia
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Jena, Am Klinikum 1, D-07747 Jena, Germany
Department of Basic Research, Institute for Atherosclerosis Research, 121609 Moscow, Russia
Department of Aging Research, Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan
Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 817;
Received: 6 December 2019 / Revised: 14 January 2020 / Accepted: 23 January 2020 / Published: 27 January 2020
(This article belongs to the Special Issue Lipoprotein Nanoparticles for Diagnosis and Therapy)
Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, 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. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response. View Full-Text
Keywords: atherosclerosis; transcriptome; lipoprotein; phagocytosis; innate immunity atherosclerosis; transcriptome; lipoprotein; phagocytosis; innate immunity
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MDPI and ACS Style

Orekhov, A.N.; Nikiforov, N.G.; Sukhorukov, V.N.; Kubekina, M.V.; Sobenin, I.A.; Wu, W.-K.; Foxx, K.K.; Pintus, S.; Stegmaier, P.; Stelmashenko, D.; Kel, A.; Gratchev, A.N.; Melnichenko, A.A.; Wetzker, R.; Summerhill, V.I.; Manabe, I.; Oishi, Y. Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis. Int. J. Mol. Sci. 2020, 21, 817.

AMA Style

Orekhov AN, Nikiforov NG, Sukhorukov VN, Kubekina MV, Sobenin IA, Wu W-K, Foxx KK, Pintus S, Stegmaier P, Stelmashenko D, Kel A, Gratchev AN, Melnichenko AA, Wetzker R, Summerhill VI, Manabe I, Oishi Y. Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis. International Journal of Molecular Sciences. 2020; 21(3):817.

Chicago/Turabian Style

Orekhov, Alexander N., Nikita G. Nikiforov, Vasily N. Sukhorukov, Marina V. Kubekina, Igor A. Sobenin, Wei-Kai Wu, Kathy K. Foxx, Sergey Pintus, Philip Stegmaier, Daria Stelmashenko, Alexander Kel, Alexei N. Gratchev, Alexandra A. Melnichenko, Reinhard Wetzker, Volha I. Summerhill, Ichiro Manabe, and Yumiko Oishi. 2020. "Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis" International Journal of Molecular Sciences 21, no. 3: 817.

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