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1.
Adv Sci (Weinh) ; 11(7): e2304690, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38064171

ABSTRACT

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12-lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add-back of MCTRs. Mechanistically, MCTR-mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR-mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.


Subject(s)
Efferocytosis , Phagocytosis , Macrophages/metabolism , Signal Transduction , Glycolysis
3.
Circ Res ; 127(5): 664-676, 2020 08 14.
Article in English | MEDLINE | ID: mdl-32434457

ABSTRACT

RATIONALE: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction. Short-term S100A9 blockade during the inflammatory phase post-myocardial infarction inhibits systemic and cardiac inflammation and improves cardiac function long term. OBJECTIVE: To evaluate the impact of S100A9 blockade on postischemic cardiac repair. METHODS AND RESULTS: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in WT (wild type) C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin-Sca-1+c-Kit+ hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150+CD48-CCR2+ hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6CloMerTKhi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes, and a larger myocardial scar. The transcription factor Nur77 (Nr4a1 [nuclear receptor subfamily 4 group A member 1]) mediates the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6Chi/int monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9-/- mice with permanent myocardial ischemia, leading to depressed cardiac function long term. CONCLUSIONS: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to myocardial infarction. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute myocardial infarction.


Subject(s)
Calgranulin B/metabolism , Hematopoietic Stem Cells/metabolism , Inflammation/metabolism , Inflammation/prevention & control , Myocardial Infarction/metabolism , Myocardium/metabolism , Neutrophils/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis , Calgranulin A/blood , Calgranulin B/blood , Calgranulin B/genetics , Cell Proliferation , Disease Models, Animal , Hematopoiesis , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Monocytes/pathology , Myocardial Infarction/drug therapy , Myocardial Infarction/immunology , Myocardial Infarction/pathology , Myocardium/immunology , Myocardium/pathology , Neutrophils/immunology , Neutrophils/pathology , Phagocytosis , Phenotype , RAW 264.7 Cells , Signal Transduction , Ventricular Function, Left , Ventricular Remodeling
4.
Cell Rep ; 24(8): 2127-2140.e7, 2018 08 21.
Article in English | MEDLINE | ID: mdl-30134173

ABSTRACT

Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other TCA cycle-derived metabolites in response to inflammatory stimulation in a glutamine-independent manner. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased circulating succinate levels. In summary, Nur77 induces an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.


Subject(s)
Gene Expression Regulation/genetics , Inflammation/metabolism , Macrophages/metabolism , Mitochondria/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Humans
5.
Arterioscler Thromb Vasc Biol ; 37(3): 423-432, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28082258

ABSTRACT

OBJECTIVE: The sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and ß (LXRß, NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters ABCA1 and ABCG1 to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. APPROACH AND RESULTS: We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of EEPD1 blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. CONCLUSIONS: In this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1.


Subject(s)
ATP Binding Cassette Transporter 1/metabolism , Cell Membrane/enzymology , Cholesterol/metabolism , Endodeoxyribonucleases/metabolism , Liver X Receptors/metabolism , Macrophages/enzymology , ATP Binding Cassette Transporter 1/genetics , Animals , Apolipoprotein A-I/metabolism , Biological Transport , COS Cells , Cell Membrane/drug effects , Chlorocebus aethiops , Endodeoxyribonucleases/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Enzymologic , HeLa Cells , Hep G2 Cells , Humans , Ligands , Liver X Receptors/agonists , Liver X Receptors/deficiency , Liver X Receptors/genetics , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RAW 264.7 Cells , RNA Interference , Transcriptome , Transfection
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