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Elevated concentrations of serum-oxidized low-density lipoproteins (oxLDL) represent a common feature of both conditions. The main goal of this study was to determine the contribution of oxLDL to the inflammatory response of macrophages exposed to diabetic-mimicking conditions. THP1 cells and peripheral blood monocytes purified from non-diabetic healthy donors were cultured under normal (5 mM) or high glucose (HG) (15 mM) with oxLDL. Then, foam cell formation, expression of CD80, HLADR, CD23, CD206, and CD163, as well as toll-like receptor 4 (TLR4) and co-receptors CD36 and CD14 (both at the cell surface and soluble (sCD14)), and inflammatory mediators\u2019 production were measured by flow cytometry, RT-qPCR, or ELISA. Additionally, serum sCD14 was determined in subjects with subclinical atherosclerosis with and without diabetes by ELISA. Our results showed that oxLDL-mediated intracellular lipid accumulation via CD36 increased under HG and that HG + oxLDL enhanced TNF, IL1B, and IL8, and decreased IL10. Moreover, TLR4 was upregulated in macrophages under HG and monocytes of subjects with diabetes and atherosclerosis. Interestingly, HG-oxLDL upregulated CD14 gene expression, although its total cellular protein abundance remained unaltered. sCD14 shedding via PRAS40\/Akt-dependent mechanisms, with pro-inflammatory activity, was significantly increased in cultured macrophages and plasma from subjects with diabetes and subclinical atherosclerosis or hypercholesterolemia. Our data support an enhanced synergistic pro-inflammatory effect induced by HG and oxLDL in cultured human macrophages, possibly explained by increased sCD14 shedding.<\/jats:p>","DOI":"10.3390\/antiox12051083","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T01:05:10Z","timestamp":1683853510000},"page":"1083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40\/Akt-Dependent Shedding of Soluble CD14"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4006-8010","authenticated-orcid":false,"given":"Luc\u00eda","family":"Sanjurjo","sequence":"first","affiliation":[{"name":"Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Castelblanco","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Unitat de Suport a la Recerca Barcelona, Institut Universitari d\u2019Investigaci\u00f3 en Atenci\u00f3 Prim\u00e0ria Jordi Gol i Gurina, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6531-2246","authenticated-orcid":false,"given":"Josep","family":"Julve","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Nutrition Group, Institut de Recerca de l\u2019Hospital de la Santa Creu i Sant Pau (IRHSCSP), 08041 Barcelona, Spain"},{"name":"Centre for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Villalmanzo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rica","family":"T\u00e9llez","sequence":"additional","affiliation":[{"name":"Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8263-1292","authenticated-orcid":false,"given":"Anna","family":"Ramirez-Morros","sequence":"additional","affiliation":[{"name":"Unitat de Suport a la Recerca Barcelona, Institut Universitari d\u2019Investigaci\u00f3 en Atenci\u00f3 Prim\u00e0ria Jordi Gol i Gurina, 08007 Barcelona, Spain"},{"name":"Ger\u00e8ncia Territorial de la Catalunya Central, Institut Catal\u00e0 de la Salut, 08272 Sant Fruit\u00f3s de Bages, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Alonso","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), ISCIII, 28029 Madrid, Spain"},{"name":"Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-0250","authenticated-orcid":false,"given":"D\u00eddac","family":"Mauricio","sequence":"additional","affiliation":[{"name":"Unitat de Suport a la Recerca Barcelona, Institut Universitari d\u2019Investigaci\u00f3 en Atenci\u00f3 Prim\u00e0ria Jordi Gol i Gurina, 08007 Barcelona, Spain"},{"name":"Centre for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), ISCIII, 28029 Madrid, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau and Sant Pau Biomedical Research Institute, 08041 Barcelona, Spain"},{"name":"Faculty of Medicine, University of Vic\u2014Central University of Catalonia, 08500 Vic, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-8069","authenticated-orcid":false,"given":"Maria-Rosa","family":"Sarrias","sequence":"additional","affiliation":[{"name":"Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, Spain"},{"name":"Centre for Biomedical Research on Liver and Digestive Diseases (CIBEREHD), ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJM199901143400207","article-title":"Atherosclerosis an Inflammatory Disease","volume":"340","author":"Ross","year":"1999","journal-title":"N. 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