Background: Adaptive immunity and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen-presenting cell antigen presentation and T-cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis.
Methods And Results: In low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, CD74 deficiency (Ldlr(-/-)Cd74(-/-)) significantly reduced atherosclerosis and CD25(+)-activated T cells in the atheromata. Although Ldlr(-/-)Cd74(-/-) mice had decreased levels of plasma immunoglobulin (Ig) G1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably as a result of impaired antigen-presenting cell function, Ldlr(-/-)Cd74(-/-) mice showed higher levels of anti-MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr(-/-)Cd74(-/-) mice had lower levels of all anti-MDA-LDL Ig isotypes compared with Ldlr(-/-) mice. As anticipated, only Ldlr(-/-) splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr(-/-) mice, but Ldlr(-/-) Cd74(-/-) mice remained protected. Compared with Ldlr(-/-) mice, Ldlr(-/-)Cd74(-/-) mice had higher anti-MDA-LDL autoantibody titers, fewer lesion CD25(+)-activated T cells, impaired release of Th1/Th2 cytokines from antigen-presenting cells after heat shock protein-65 stimulation, and reduced levels of all plasma anti-heat shock protein-65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL- or heat shock protein-65-immunized mice showed increased percentages of autoantibody-producing marginal zone B and B-1 cells in Ldlr(-/-)Cd74(-/-) mice compared with Ldlr(-/-) mice.
Conclusions: Invariant chain deficiency in Ldlr(-/-) mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, an unexpected increase in the number of innate-like peripheral B-1 cell populations occurred, resulting in increased IgM/IgG3 titers to the oxidation-specific epitopes.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927799 | PMC |
| http://dx.doi.org/10.1161/CIRCULATIONAHA.109.891887 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Reduction of Low-Density Lipoprotein Cholesterol by Mesenchymal Stem Cells in a Mouse Model of Exogenous Cushing's Syndrome.
Tissue Eng Regen Med
January 2025
Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul, 07804, South Korea.
Background: Exogenous Cushing's syndrome, which results from prolonged glucocorticoid treatment, is associated with metabolic abnormalities. Previously, we reported the inhibitory effect of tonsil-derived mesenchymal stem cell conditioned medium (T-MSC CM) on glucocorticoid signal transduction. In this study, we investigated the therapeutic efficacy of T-MSCs in a mouse model of exogenous Cushing's syndrome.
View Article and Find Full Text PDFChronic stress-induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response.
Proc Natl Acad Sci U S A
February 2025
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China.
Recent studies have demonstrated that chronic stress can enhance the development of multiple human diseases, including cancer. However, the role of chronic stress in esophageal carcinogenesis and its underlying molecular mechanisms remain unclear. This study uncovered that dysregulated cholesterol metabolism significantly promotes esophageal carcinogenesis under chronic stress conditions.
View Article and Find Full Text PDFBackground: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality in the western world despite the success of lipid lowering therapies, highlighting the need for novel lipid-independent therapeutic strategies. Genome-wide association studies (GWAS) have identified numerous genes associated with ASCVD that function in the vessel wall, suggesting that vascular cells mediate ASCVD, and that the genes and pathways essential for this vascular cell function may be novel therapeutic targets for the treatment of ASCVD. Furthermore, some of these implicated genes appear to function in the adventitial layer of the vasculature, suggesting these cells are able to potentiate ASCVD.
View Article and Find Full Text PDFETV5-Mediated Transcriptional Repression of DDIT4 Blocks Macrophage Pro-Inflammatory Activation in Diabetic Atherosclerosis.
Cardiovasc Toxicol
January 2025
Department of Cadre Ward, The First Affiliated Hospital of Harbin Medical University, No. 23, Postal Street, Harbin, 150001, Heilongjiang, PR China.
Atherosclerosis risk is elevated in diabetic patients, but the underlying mechanism such as the involvement of macrophages remains unclear. Here, we investigated the underlying mechanism related to the pro-inflammatory activation of macrophages in the development of diabetic atherosclerosis. Bioinformatics tools were used to analyze the macrophage-related transcriptome differences in patients with atherosclerosis and diabetic mice.
View Article and Find Full Text PDFOlivetol's Effects on Metabolic State and Gut Microbiota Functionality in Mouse Models of Alimentary Obesity, Diabetes Mellitus Type 1 and 2, and Hypercholesterolemia.
Biomedicines
January 2025
Department of Biochemistry and Molecular Biology, Faculty of Medicine, FSAEI HE N. I. Pirogov Russian National Research Medical University of MOH of Russia, 1 Ostrovitianov Str., 117997 Moscow, Russia.
Background: Disorders of glucose and lipid metabolism, such as obesity, diabetes mellitus, or hypercholesterolemia, can cause serious complications, reduce quality of life, and lead to increased premature mortality. Olivetol, a natural compound, could be proposed as a promising therapeutic agent for preventing, treating, or alleviating metabolic complications of such pathological conditions.
Methods: In this study, the researchers conducted a broad parallel investigation of olivetol's effects on metabolic state and gut microbiota functionality in mouse models of alimentary obesity, diabetes mellitus type 1 and 2, and hypercholesterolemia.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!