CD40-TRAF6, mTOR and S6K1 targeted inhibition of macrophage dynamics resolves atherosclerotic plaque inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104777 | GEO | 2017/10/11
REPOSITORIES: GEO
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Project description:Background: The co-stimulatory CD40-CD40L dyad is an important driver of atherosclerosis. CD40 exerts divergent, cell-specific roles, which differentially impact atherogenesis. Objectives: We here investigate the role of the most prominent CD40-expressing cell-type, the B-cell, in atherosclerosis. Methods: B-cell subset specific CD40-expression of patients with mild and severe coronary artery disease (CAD) was determined by mass-cytometry and correlated to CAD severity. Underlying mechanisms were elucidated using B-cell CD40-deficient CD19Cre-CD40flfl-ApoE-/-(CD40BKO) mice and control littermates (CD40BWT). Results: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis. Conclusions: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis.
2024-10-19 | GSE186134 | GEO
Project description:Inhibition of the costimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage can result in immune suppression. We recently identified small molecule inhibitors that block the interaction between CD40 and TNF Receptor Associated Factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. Here we further characterized the working mechanisms of TRAF-STOPs 6877002 and 6860766 in atherogenesis. Transcriptional profiling in CD40-activated macrophages showed that TRAF-STOP 6877002 had profound effects on the clusters ‘immune responses’ and ‘cell cycle progression’, whereas TRAF-STOP 6860766 only affected ‘immune responses’.
2018-01-15 | GSE90835 | GEO
Project description:Atherosclerosis, the underlying vascular cause of cardiovascular disease, has a strong inflammatory component. The co-stimulatory CD40-CD40 ligand (CD40L) signaling axis is a pivotal regulator of immune responses in atherosclerosis. However, therapeutic long-term inhibition of CD40L will severely compromise the immune system making it a non-viable treatment option. To circumvent this issue, cell-specific inhibition may present a better approach to target the CD40-CD40L axis. Therefore, we generated T cell and platelet-specific knockout mice for CD40L and apolipoprotein E, which were aged for 28 weeks to study their effects on immune status and atherosclerosis. Here, we show that T cell specific deficiency in CD40L signaling reduced plaque progression through hampered Th1 polarization as well as reduced antigen-dependent proliferation and oxLDL IgM production. DC-specific CD40 deficient mice displayed a similar phenotype. Platelet-specific CD40L deficiency, however, failed to decrease atherosclerosis, but ameliorated atherothrombosis. Together, our results illuminate the divergent cell-specific mechanisms of CD40-CD40L signaling in atherosclerosis, which may lead to advances in targeted therapies.
2021-03-16 | GSE145585 | GEO
Project description:Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. Interleukin-17A is a pro-inflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. 26-weeks old apolipoprotein E-deficient (Apoe-/-) mice were fed a standard chow diet and treated either with IL-17A mAb (n=15) or irrelevant immunoglobulin (n=10) for 16 weeks. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (P=0.001) by reducing inflammatory burden and cellular infiltration (P=0.01) and improved lesion stability (P=0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, sensitization of antigen-presenting cells toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a pro-inflammatory milieu and up-regulation of molecules expressed by the IL-17A-induced macrophage subtype. We here show for the first time that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in Apoe-/- mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte / macrophage lineage. In addition, translational experiments underline the relevance for the human system. Effects of IL-17A on human monocyte-derived macrophages were assessed (n=2 per group).
2014-10-01 | E-GEOD-60824 | biostudies-arrayexpress
Project description:In atherosclerosis progression and regression, monocytes or monocyte-derived macrophages are the major immune cells in the plaque. It is important to understand the fate and characteristics of monocyte/macrophage during the plaque progression and regression. To characterize the fate of monocytes/macrophages, we performed single cell RNA sequencing of fate-mapped aortic CX3CR1-derived monocytes/macrophages from Cx3cr1CreERT2-IRES-YFP/+Rosa26floxed-tdTomato/+ mice with AAV-PCSK9 injection and fed a Western Diet. The single cell RNA-seq analyses revealed the heterogeneity of aortic macrophages and identified a stem-like cell cluster in atherosclerotic aorta.
2019-02-21 | GSE123587 | GEO
Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.
2020-05-12 | GSE145200 | GEO
Project description:Trained immunity refers to epigenetic and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to a heightened response to secondary stimuli. Although this innate immune memory contributes to host defense against infections, it can also have maladaptive consequences in a broad range of immune-driven conditions. During the past decade, we have gained an increasingly better understanding of the molecular regulation of trained immunity, but the role of adaptive immune cells in modulation of trained immunity remains largely unknown. Here, we show that T cell interactions contribute to the induction of trained immunity in monocytes and that this mediated by CD40-TRAF6 signaling. Specifically, we found that inhibiting CD40-TRAF6 signaling prevents the induction of functional, transcriptomic, metabolic and epigenetic changes associated with trained immunity. Apart from detailed in vitro studies, we inhibited CD40-TRAF6 signaling in vivo in myeloid cells in a murine heart transplantation model which resulted in prolonged allograft survival. When the animals were additionally treated with costimulatory blockade by CTLA4-Ig, we observed immunological tolerance to the graft. Combined, our study reveals that trained immunity induction is regulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells, and that this signaling can be efficiently leveraged for therapeutic purposes.
2024-08-26 | GSE228182 | GEO
Project description:Trained immunity refers to epigenetic and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to a heightened response to secondary stimuli. Although this innate immune memory contributes to host defense against infections, it can also have maladaptive consequences in a broad range of immune-driven conditions. During the past decade, we have gained an increasingly better understanding of the molecular regulation of trained immunity, but the role of adaptive immune cells in modulation of trained immunity remains largely unknown. Here, we show that T cell interactions contribute to the induction of trained immunity in monocytes and that this mediated by CD40-TRAF6 signaling. Specifically, we found that inhibiting CD40-TRAF6 signaling prevents the induction of functional, transcriptomic, metabolic and epigenetic changes associated with trained immunity. Apart from detailed in vitro studies, we inhibited CD40-TRAF6 signaling in vivo in myeloid cells in a murine heart transplantation model which resulted in prolonged allograft survival. When the animals were additionally treated with costimulatory blockade by CTLA4-Ig, we observed immunological tolerance to the graft. Combined, our study reveals that trained immunity induction is regulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells, and that this signaling can be efficiently leveraged for therapeutic purposes.
2024-08-26 | GSE228183 | GEO
Project description:B1b cell homeostasis is maintained by CD40 in atherosclerosis
| PRJNA772716 | ENA
Project description:Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. Interleukin-17A is a pro-inflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. 26-weeks old apolipoprotein E-deficient (Apoe-/-) mice were fed a standard chow diet and treated either with IL-17A mAb (n=15) or irrelevant immunoglobulin (n=10) for 16 weeks. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (P=0.001) by reducing inflammatory burden and cellular infiltration (P=0.01) and improved lesion stability (P=0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, sensitization of antigen-presenting cells toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a pro-inflammatory milieu and up-regulation of molecules expressed by the IL-17A-induced macrophage subtype. We here show for the first time that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in Apoe-/- mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte / macrophage lineage. In addition, translational experiments underline the relevance for the human system.
2014-10-01 | GSE60824 | GEO