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Arteriosclerosis, Thrombosis, and... Jan 2020Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery... (Review)
Review
Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerosis. In each vascular bed, macrophages contribute to the maintenance of the local inflammatory response, propagate plaque development, and promote thrombosis. These central roles, coupled with their plasticity, makes macrophages attractive therapeutic targets in stemming the development of and stabilizing existing atherosclerosis. In the context of ASCVD, classically activated M1 macrophages initiate and sustain inflammation, and alternatively activated M2 macrophages resolve inflammation. However, this classification is now considered an oversimplification, and a greater understanding of plaque macrophage physiology in ASCVD is required to aid in the development of therapeutics to promote ASCVD regression. Reviewed herein are the macrophage phenotypes and molecular regulators characteristic of ASCVD regression, and the current murine models of ASCVD regression.
Topics: Animals; Atherosclerosis; Coronary Artery Disease; Disease Progression; Humans; Leukocyte Count; Macrophage Activation; Macrophages; Phenotype; Plaque, Atherosclerotic
PubMed: 31722535
DOI: 10.1161/ATVBAHA.119.312802 -
BMC Immunology Jun 2020Macrophage M1 polarization plays a pivotal role in inflammatory diseases. Progranulin (PGRN) has potential anti-inflammation action, however, the effect of PGRN on...
BACKGROUND
Macrophage M1 polarization plays a pivotal role in inflammatory diseases. Progranulin (PGRN) has potential anti-inflammation action, however, the effect of PGRN on macrophage M1 polarization has been poorly studied. Our study aimed to investigate the effect of PGRN on lipopolysaccharide (LPS)-induced macrophage M1 polarization and clarify the underlying mechanisms.
METHODS
RAW264.7 cells were polarized to M1 macrophage by LPS with or without recombinant PGRN (rPGRN) and tumor necrosis factor alpha antibody (anti-TNF-α). A cell counting kit-8 assay (CCK-8), flow cytometry, Quantitative Real-Time PCR assay (q-PCR), Western blot assay and enzyme-linked immunosorbent assay (ELISA) were used to determine the effect of different treatments on cell proliferation, expression of surface phenotype marker and expressions and secretion of inflammatory cytokines. The activation of NF-κB/mitogen-activated protein kinase (MAPK) pathways and the nuclear translocation of NF-κB p65 were detected by Western blot and immunofluorescence respectively. THP-1 and primary bone marrow-derived monocytes (BMDMs) were also used to demonstrate effect of PGRN on expressions and secretion of inflammatory cytokines induced by LPS.
RESULTS
In RAW264.7 cells, rPGRN at concentrations below 80 ng/ml significantly promoted cell proliferation in dose dependent fashion. rPGRN significantly inhibited LPS-induced change of phenotype (CD86/CD206 ratio) and function (tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) expressions). LPS-stimulated secretion of TNF-α and activated phosphorylation of IKKα/β, IкBα, p65, JNK and p38 and the nucleus translocation of NF-кB p65 were also significantly downregulated by rPGRN. In addition, recombinant TNF-α (rTNF-α) significantly boosted TNF-α and iNOS expression vs the control group. Moreover, anti-TNF-α significantly inhibited LPS-induced TNF-α and iNOS expression. In THP-1 and BMDM cells, reversing effect of rPGRN on LPS-enhanced expressions of TNF-α and iNOS and secretion of TNF-α was further demonstrated.
CONCLUSIONS
PGRN down-regulates LPS-induced macrophage M1 polarization in phenotype and function via NF-κB/MAPK signaling pathways.
Topics: Animals; Biomarkers; Cell Line; Cell Proliferation; Cytokines; Humans; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; Progranulins; RAW 264.7 Cells; THP-1 Cells; Transcription Factor RelA; Tumor Necrosis Factor-alpha
PubMed: 32503416
DOI: 10.1186/s12865-020-00355-y -
Cell Feb 2021Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of...
Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.
Topics: Black or African American; Aging; Alleles; Animals; Cohort Studies; Erythrocyte Count; Erythropoiesis; Gain of Function Mutation; Hepatocytes; Hepcidins; Humans; Ion Channels; Iron; Iron Overload; Macrophages; Mechanotransduction, Cellular; Mice, Inbred C57BL; Phagocytosis; Phenotype; Stress, Physiological; Mice
PubMed: 33571427
DOI: 10.1016/j.cell.2021.01.024 -
The Journal of Clinical Investigation Jul 2022Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (Jak2VF) mutation increases cardiovascular...
Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (Jak2VF) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2VF mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid Jak2VF expression promotes atherosclerosis, we developed hyperlipidemic erythropoietin receptor Cre mice that express Jak2VF in the erythroid lineage (VFEpoR mice). VFEpoR mice without elevated blood cell counts showed increased atherosclerotic plaque necrosis, erythrophagocytosis, and ferroptosis. Selective induction of erythrocytosis with low-dose erythropoietin further exacerbated atherosclerosis with prominent ferroptosis, lipid peroxidation, and endothelial damage. VFEpoR RBCs had reduced antioxidant defenses and increased lipid hydroperoxides. Phagocytosis of human or murine WT or JAK2VF RBCs by WT macrophages induced ferroptosis, which was prevented by the ferroptosis inhibitor liproxstatin-1. Liproxstatin-1 reversed increased atherosclerosis, lipid peroxidation, ferroptosis, and endothelial damage in VFEpoR mice and in Jak2VF chimeric mice simulating clonal hematopoiesis, but had no impact in controls. Erythroid lineage Jak2VF expression led to qualitative and quantitative defects in RBCs that exacerbated atherosclerosis. Phagocytosis of RBCs by plaque macrophages promoted ferroptosis, suggesting a therapeutic target for reducing RBC-mediated cardiovascular risk.
Topics: Animals; Atherosclerosis; Cell Lineage; Ferroptosis; Lymphohistiocytosis, Hemophagocytic; Macrophages; Mice; Phagocytosis; Plaque, Atherosclerotic
PubMed: 35587375
DOI: 10.1172/JCI155724 -
Nature Communications Aug 2022Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide...
Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide clues for the establishment of new biomarkers and therapeutic approaches targeting post-MI HF. Here, we investigate the spatiotemporal dynamics of MI-associated immune cells in a mouse model of MI using spatial transcriptomics and single-cell RNA-sequencing (scRNA-seq). We identify twelve major immune cell populations; their proportions dynamically change after MI. Macrophages are the most abundant population at all-time points (>60%), except for day 1 post-MI. Trajectory inference analysis shows upregulation of Trem2 expression in macrophages during the late phase post-MI. In vivo injection of soluble Trem2 leads to significant functional and structural improvements in infarcted hearts. Our data contribute to a better understanding of MI-driven immune responses and further investigation to determine the regulatory factors of the Trem2 signaling pathway will aid the development of novel therapeutic strategies for post-MI HF.
Topics: Animals; Biomarkers; Disease Models, Animal; Heart Failure; Leukocyte Count; Macrophages; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Receptors, Immunologic
PubMed: 35933399
DOI: 10.1038/s41467-022-32284-2 -
Nature Communications Nov 2022Macrophages are involved in tissue homeostasis and are critical for innate immune responses, yet distinct macrophage populations in different tissues exhibit diverse...
Macrophages are involved in tissue homeostasis and are critical for innate immune responses, yet distinct macrophage populations in different tissues exhibit diverse gene expression patterns and biological processes. While tissue-specific macrophage epigenomic and transcriptomic profiles have been reported, proteomes of different macrophage populations remain poorly characterized. Here we use mass spectrometry and bulk RNA sequencing to assess the proteomic and transcriptomic patterns, respectively, of 10 primary macrophage populations from seven mouse tissues, bone marrow-derived macrophages and the cell line RAW264.7. The results show distinct proteomic landscape and protein copy numbers between tissue-resident and recruited macrophages. Construction of a hierarchical regulatory network finds cell-type-specific transcription factors of macrophages serving as hubs for denoting tissue and functional identity of individual macrophage subsets. Finally, Il18 is validated to be essential in distinguishing molecular signatures and cellular function features between tissue-resident and recruited macrophages in the lung and liver. In summary, these deposited datasets and our open proteome server ( http://macrophage.mouseprotein.cn ) integrating all information will provide a valuable resource for future functional and mechanistic studies of mouse macrophages.
Topics: Mice; Animals; Proteomics; Transcriptome; Macrophages; Proteome; Leukocyte Count
PubMed: 36450731
DOI: 10.1038/s41467-022-35095-7 -
Circulation Research Jan 2021Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease...
RATIONALE
Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease.
OBJECTIVE
To test whether and how eosinophils affect AAA growth.
METHODS AND RESULTS
Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 10/L, <0.001). Univariate (odds ratio, 1.381, <0.001) and multivariate (odds ratio, 1.237, =0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in and eosinophil-deficient ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11bLy6C monocytes, and increased CD11bLy6C monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and mice, but not eosinophil from mice, blocked AAA growth in ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells.
CONCLUSIONS
Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.
Topics: Adoptive Transfer; Aged; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Eosinophils; Female; Humans; Inflammation Mediators; Interleukin-10; Interleukin-4; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocytes; NF-kappa B; Phenotype; Ribonucleases; Vascular Remodeling; Mice
PubMed: 33153394
DOI: 10.1161/CIRCRESAHA.120.318182 -
Nature May 2021Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal...
Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease. Many of the underlying causal variants may affect enhancers, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.
Topics: Cell Line; Chromosomes, Human, Pair 10; Cyclophilins; Dendritic Cells; Enhancer Elements, Genetic; Female; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases; Macrophages; Male; Mitochondria; Organ Specificity; Phenotype
PubMed: 33828297
DOI: 10.1038/s41586-021-03446-x -
Gut Sep 2020High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally...
OBJECTIVE
High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.
DESIGN
Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.
RESULTS
Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus and , both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of and sperm motility, and a positive correlation between blood endotoxin and abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.
CONCLUSION
We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.
TRIAL REGISTRATION NUMBER
NCT03634644.
Topics: Animals; Bacteroides; Correlation of Data; Cytokines; Diet, High-Fat; Dysbiosis; Endotoxemia; Epididymis; Feces; Gastrointestinal Microbiome; Humans; Macrophages; Male; Mice; Prevotella; Sperm Motility; Spermatogenesis; T-Lymphocytes
PubMed: 31900292
DOI: 10.1136/gutjnl-2019-319127 -
Pharmacological Research Feb 2022The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu...
The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-β as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications.
Topics: Acute Lung Injury; Animals; COVID-19; Cell Line; China; Cytokines; Drugs, Chinese Herbal; Interleukin-17; Leukocyte Count; Macrophages; Male; Mice; Mice, Inbred C57BL; Neutrophils; Programmed Cell Death 1 Receptor; RAW 264.7 Cells; Signal Transduction; COVID-19 Drug Treatment
PubMed: 35033647
DOI: 10.1016/j.phrs.2022.106083