Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14
Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. 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 inflamm...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/5/1083 |
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| author | Lucía Sanjurjo Esmeralda Castelblanco Josep Julve Nuria Villalmanzo Érica Téllez Anna Ramirez-Morros Núria Alonso Dídac Mauricio Maria-Rosa Sarrias |
| author_facet | Lucía Sanjurjo Esmeralda Castelblanco Josep Julve Nuria Villalmanzo Érica Téllez Anna Ramirez-Morros Núria Alonso Dídac Mauricio Maria-Rosa Sarrias |
| author_sort | Lucía Sanjurjo |
| collection | DOAJ |
| description | Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. 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’ 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. |
| first_indexed | 2024-03-11T03:59:36Z |
| format | Article |
| id | doaj.art-6caaae6d31f84132b9cd7fc6904470fd |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T03:59:36Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-6caaae6d31f84132b9cd7fc6904470fd2023-11-18T00:15:19ZengMDPI AGAntioxidants2076-39212023-05-01125108310.3390/antiox12051083Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14Lucía Sanjurjo0Esmeralda Castelblanco1Josep Julve2Nuria Villalmanzo3Érica Téllez4Anna Ramirez-Morros5Núria Alonso6Dídac Mauricio7Maria-Rosa Sarrias8Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, SpainDivision of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USAEndocrinology, Diabetes and Nutrition Group, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau (IRHSCSP), 08041 Barcelona, SpainDepartment of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, 08916 Badalona, SpainInnate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, SpainUnitat de Suport a la Recerca Barcelona, Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina, 08007 Barcelona, SpainCentre for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), ISCIII, 28029 Madrid, SpainUnitat de Suport a la Recerca Barcelona, Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina, 08007 Barcelona, SpainInnate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), 08916 Badalona, SpainAtherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. 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’ 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.https://www.mdpi.com/2076-3921/12/5/1083diabetesatherosclerosisCD36foam cellmonocytesTLR4 |
| spellingShingle | Lucía Sanjurjo Esmeralda Castelblanco Josep Julve Nuria Villalmanzo Érica Téllez Anna Ramirez-Morros Núria Alonso Dídac Mauricio Maria-Rosa Sarrias Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 Antioxidants diabetes atherosclerosis CD36 foam cell monocytes TLR4 |
| title | Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 |
| title_full | Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 |
| title_fullStr | Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 |
| title_full_unstemmed | Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 |
| title_short | Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14 |
| title_sort | contribution of elevated glucose and oxidized ldl to macrophage inflammation a role for pras40 akt dependent shedding of soluble cd14 |
| topic | diabetes atherosclerosis CD36 foam cell monocytes TLR4 |
| url | https://www.mdpi.com/2076-3921/12/5/1083 |
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