دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis.
المؤلفون: Orekhov AN; 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., Nikiforov NG; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 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., Sukhorukov VN; 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., Kubekina MV; Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, 119334 Moscow, Russia., Sobenin IA; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia.; Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, 121552 Moscow, Russia., Wu WK; Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan., Foxx KK; Kalen Biomedical, LLC, 20886 Montgomery Village, MD, USA., Pintus S; BIOSOFT.RU, LLC, Novosibirsk 630090, Russia.; Institute of Computational Technologies, 630090 Novosibirsk, Russia., Stegmaier P; geneXplain GmbH, 38302 Wolfenbüttel, Germany., Stelmashenko D; BIOSOFT.RU, LLC, Novosibirsk 630090, Russia.; geneXplain GmbH, 38302 Wolfenbüttel, Germany., Kel A; BIOSOFT.RU, LLC, Novosibirsk 630090, Russia.; geneXplain GmbH, 38302 Wolfenbüttel, Germany.; Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia., Gratchev AN; N. N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoye sh.,115478 Moscow, Russia., Melnichenko AA; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia.; Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, 121552 Moscow, Russia., Wetzker R; Department of Anaesthesiology and Intensive Care Medicine, University Hospital Jena, Am Klinikum 1, D-07747 Jena, Germany., Summerhill VI; Department of Basic Research, Institute for Atherosclerosis Research, 121609 Moscow, Russia., Manabe I; Department of Aging Research, Graduate school of Medicine, Chiba University, Chiba, Japan., Oishi Y; Department of Biochemistry & Molecular Biology, Nippon Medical School, 113-8602 Tokyo, Japan.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2020 Jan 27; Vol. 21 (3). Date of Electronic Publication: 2020 Jan 27.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Phagocytosis*/genetics , Phagocytosis*/immunology, Foam Cells/*metabolism , Foam Cells/*pathology , Lipoproteins, LDL/*metabolism, Biomarkers ; Foam Cells/immunology ; Gene Expression Profiling ; Gene Knockdown Techniques ; Humans ; Immunity, Innate ; Lipid Metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Monocytes/immunology ; Monocytes/metabolism ; Oxidation-Reduction ; Signal Transduction ; Transcriptome
مستخلص: 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.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: 19-15-00010 Russian Science Foundation
فهرسة مساهمة: Keywords: atherosclerosis; innate immunity; lipoprotein; phagocytosis; transcriptome
المشرفين على المادة: 0 (Biomarkers)
0 (Lipoproteins, LDL)
تواريخ الأحداث: Date Created: 20200205 Date Completed: 20201103 Latest Revision: 20201103
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7037225
DOI: 10.3390/ijms21030817
PMID: 32012706
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms21030817