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2.
Cell Death Dis ; 12(6): 533, 2021 05 25.
Article de Anglais | MEDLINE | ID: mdl-34031369

RÉSUMÉ

Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-κB signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.


Sujet(s)
Antigènes de surface/physiologie , Chondrocytes/physiologie , Macrophages/physiologie , Arthrose/génétique , Animaux , Antigènes de surface/génétique , Cellules cultivées , Reprogrammation cellulaire/génétique , Vieillissement de la cellule/génétique , Chondrocytes/anatomopathologie , Femelle , Humains , Macrophages/anatomopathologie , Mâle , Souris , Souris de lignée C57BL , microARN/physiologie , Protéines de lait/génétique , Facteur de transcription NF-kappa B/métabolisme , Arthrose/anatomopathologie , Cellules RAW 264.7 , Transduction du signal/génétique
3.
Biochem Soc Trans ; 49(1): 441-453, 2021 02 26.
Article de Anglais | MEDLINE | ID: mdl-33616615

RÉSUMÉ

Glycosylation represents one of the most abundant posttranslational modification of proteins. Glycosylation products are diverse and are regulated by the cooperative action of various glycosyltransferases, glycosidases, substrates thereof: nucleoside sugars and their transporters, and chaperons. In this article, we focus on a glycosyltransferase, α1,6-fucosyltransferase (Fut8) and its product, the core fucose structure on N-glycans, and summarize the potential protective functions of this structure against emphysema and chronic obstructive pulmonary disease (COPD). Studies of FUT8 and its enzymatic product, core fucose, are becoming an emerging area of interest in various fields of research including inflammation, cancer and therapeutics. This article discusses what we can learn from studies of Fut8 and core fucose by using knockout mice or in vitro studies that were conducted by our group as well as other groups. We also include a discussion of the potential protective functions of the keratan sulfate (KS) disaccharide, namely L4, against emphysema and COPD as a glycomimetic. Glycomimetics using glycan analogs is one of the more promising therapeutics that compensate for the usual therapeutic strategy that involves targeting the genome and the proteome. These typical glycans using KS derivatives as glycomimetics, will likely become a clue to the development of novel and effective therapeutic strategies.


Sujet(s)
Matériaux biomimétiques/usage thérapeutique , Kératane sulfate/composition chimique , Broncho-pneumopathie chronique obstructive/traitement médicamenteux , Animaux , Antigènes CD/génétique , Antigènes CD/métabolisme , Antigènes de surface/génétique , Antigènes de surface/métabolisme , Antigènes de surface/physiologie , Matériaux biomimétiques/composition chimique , Fucose/métabolisme , Fucosyltransferases/physiologie , Glycosylation , Humains , Lectines de type C/antagonistes et inhibiteurs , Lectines de type C/génétique , Lectines de type C/métabolisme , Lectines de type C/physiologie , Lectines liant le mannose/antagonistes et inhibiteurs , Lectines liant le mannose/génétique , Lectines liant le mannose/métabolisme , Lectines liant le mannose/physiologie , Souris , Souris knockout , Thérapie moléculaire ciblée/méthodes , Polyosides/composition chimique , Polyosides/métabolisme , Broncho-pneumopathie chronique obstructive/génétique , Broncho-pneumopathie chronique obstructive/métabolisme
4.
J Cell Mol Med ; 24(16): 9300-9312, 2020 08.
Article de Anglais | MEDLINE | ID: mdl-32648659

RÉSUMÉ

In our previous studies, we reported that myeloid differentiation protein 1 (MD1) serves as a negative regulator in several cardiovascular diseases. However, the role of MD1 in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain unclear. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice served as models of HFpEF induced by uninephrectomy, continuous saline or d-aldosterone infusion and a 1.0% sodium chloride treatment in drinking water for 4 weeks to investigate the effect of MD1 on HFpEF in vivo. H9C2 cells were treated with aldosterone to evaluate the role of MD1 KO in vitro. MD1 expression was down-regulated in the HFpEF mice; HFpEF significantly increased the levels of intracellular reactive oxygen species (ROS) and promoted autophagy; and in the MD1-KO mice, the HFpEF-induced intracellular ROS and autophagy effects were significantly exacerbated. Moreover, MD1 loss activated the p38-MAPK pathway both in vivo and in vitro. Aldosterone-mediated cardiomyocyte autophagy was significantly inhibited in cells pre-treated with the ROS scavenger N-acetylcysteine (NAC) or p38 inhibitor SB203580. Furthermore, inhibition with the autophagy inhibitor 3-methyladenine (3-MA) offset the aggravating effect of aldosterone-induced autophagy in the MD1-KO mice and cells both in vivo and in vitro. Our results validate a critical role of MD1 in the pathogenesis of HFpEF. MD1 deletion exaggerates cardiomyocyte autophagy in HFpEF via the activation of the ROS-mediated MAPK signalling pathway.


Sujet(s)
Antigènes de surface/physiologie , Autophagie , Défaillance cardiaque/anatomopathologie , Système de signalisation des MAP kinases , Glycoprotéines membranaires/physiologie , Stress oxydatif , Espèces réactives de l'oxygène/métabolisme , Débit systolique , Animaux , Défaillance cardiaque/étiologie , Défaillance cardiaque/métabolisme , Mâle , Souris , Souris de lignée C57BL , Souris knockout , Myocytes cardiaques/métabolisme , Myocytes cardiaques/anatomopathologie , Transduction du signal , Remodelage ventriculaire
5.
Life Sci ; 254: 117746, 2020 Aug 01.
Article de Anglais | MEDLINE | ID: mdl-32376266

RÉSUMÉ

AIMS: Transmembrane 4 L six family member 1 (TM4SF1) is a small plasma membrane glycoprotein that is highly expressed in cancers. However, the role of TM4SF1 that plays in keloids remains unknown. We investigated the expression, function and the microRNA (miRNA) regulatory network of TM4SF1 in keloids. MAIN METHODS: Small interfering RNAs and lentivirus were used to alter the expression of TM4SF1 in fibroblasts. Dual-luciferase reporter assays were applied to determine the miRNA targets. Immunohistochemistry, western blotting, qRT-PCR, wound healing assays, Transwell assays, cell count kit-8 assays and flow cytometry were also employed in this study. KEY FINDINGS: TM4SF1 was frequently upregulated in human keloid fibroblasts (HKFs) compared with human normal skin fibroblasts (HSFs). The downregulation of TM4SF1 significantly inhibited proliferation and migration, and induced apoptosis in HKFs. Furthermore, si-TM4SF1 inhibited the AKT/ERK signaling. Meanwhile, the upregulation of TM4SF1 promoted proliferation, migration and the activation of AKT/ERK signaling in human foreskin fibroblasts (HFF-1). Moreover, TM4SF1 can be regulated by miRNAs, which have been validated to play important roles in keloids by posttranscriptional regulation of gene expression. After screening, we found miR-1-3p and miR-214-5p targeted TM4SF1, inhibited TM4SF1 expression, cell proliferation, migration, and induced apoptosis in HKFs. And the level of miR-1-3p and miR-214-5p were found lower in HKFs than in HSFs. SIGNIFICANCE: Our study demonstrates a novel regulatory mechanism by which miR-1-3p, miR-214-5p, and TM4SF1 are involved in proliferation, cell motility, and apoptosis, suggesting that they may be potential targets in therapies for keloids.


Sujet(s)
Antigènes de surface/physiologie , Mouvement cellulaire/physiologie , Prolifération cellulaire/physiologie , Extracellular Signal-Regulated MAP Kinases/métabolisme , Chéloïde/anatomopathologie , microARN/métabolisme , Protéines tumorales/physiologie , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signal , Humains , Chéloïde/métabolisme
6.
PLoS Biol ; 17(12): e3000549, 2019 12.
Article de Anglais | MEDLINE | ID: mdl-31815943

RÉSUMÉ

Dose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here, we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. These densities are robustly quantifiable, a major advance over previous studies. We validate the system for a range of immunoreceptors, including the T-cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. We also extend our work to the activation of chimeric antigen receptors. This novel system allows the effect of varying the surface density, valency, dimensions, and affinity of the ligand to be investigated. It can be readily broadened to other receptor-cell surface ligand interactions and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.


Sujet(s)
Antigènes de surface/physiologie , Dosage biologique/méthodes , Communication cellulaire/immunologie , Animaux , Cellules CHO , Cricetulus , Cellules HEK293 , Humains , Cellules Jurkat , Ligands , Activation des lymphocytes/immunologie , Récepteurs aux antigènes des cellules T/immunologie , Transduction du signal/immunologie , Cellules THP-1
7.
Viruses ; 11(11)2019 11 03.
Article de Anglais | MEDLINE | ID: mdl-31684192

RÉSUMÉ

As a canonical lymphocyte antigen-6/urokinase-type plasminogen activator receptor Ly6/uPAR family protein, lymphocyte antigen 6 complex, locus E (LY6E), plays important roles in immunological regulation, T cell physiology, and oncogenesis. Emerging evidence indicates that LY6E is also involved in the modulation of viral infection. Consequently, viral infection and associated pathogenesis have been associated with altered LY6E gene expression. The interaction between viruses and the host immune system has offered insights into the biology of LY6E. In this review, we summarize the current knowledge of LY6E in the context of viral infection, particularly viral entry.


Sujet(s)
Antigènes de surface/physiologie , Maladies virales/virologie , Phénomènes physiologiques viraux , Animaux , Antigènes de surface/génétique , Antigènes de surface/métabolisme , Protéines liées au GPI/génétique , Protéines liées au GPI/métabolisme , Protéines liées au GPI/physiologie , Interactions hôte-pathogène , Humains , Récepteurs de surface cellulaire/métabolisme , Spécificité d'espèce , Maladies virales/métabolisme , Pénétration virale , Virus/classification , Virus/métabolisme
8.
Med Sci Monit ; 25: 7898-7907, 2019 Oct 22.
Article de Anglais | MEDLINE | ID: mdl-31636246

RÉSUMÉ

BACKGROUND Myocardial apoptosis and inflammation play important roles in doxorubicin (DOX)-caused cardiotoxicity. Our prior studies have characterized the effects of myeloid differentiation protein 1(MD-1) in pathological cardiac remodeling and myocardial ischemia/reperfusion (I/R) injury, but its participations and potential molecular mechanisms in DOX-caused cardiotoxicity remain unknown. MATERIAL AND METHODS In the present study, MD-1 knockout mice were generated, and a single intraperitoneal injection of DOX (15 mg/kg) was performed to elicit DOX-induced cardiotoxicity. Cardiac function, histological change, mitochondrial structure, myocardial death, apoptosis, inflammation, and molecular alterations were measured systemically. RESULTS The results showed that the protein and mRNA levels of MD-1 were dramatically downregulated in DOX-treated cardiomyocytes. DOX insult markedly accelerated cardiac dysfunction and injury, followed by enhancements of apoptosis and inflammation, all of which were further aggravated in MD-1 knockout mice. Mechanistically, the TLR4/MAPKs/NF-kappaB pathways, which were over-activated in MD-1-deficient mice, were significantly increased in DOX-damaged cardiomyocytes. Moreover, the abolishment of TLR4 or NF-kappaB via a specific inhibitor exerted protective effects against the adverse effects of MD-1 loss on DOX-caused cardiotoxicity. CONCLUSIONS Collectively, these findings suggest that MD-1 is a novel target for the treatment of DOX-induced cardiotoxicity.


Sujet(s)
Antigènes de surface/métabolisme , Cardiotoxicité/métabolisme , Glycoprotéines membranaires/métabolisme , Myocytes cardiaques/métabolisme , Animaux , Antigènes de surface/génétique , Antigènes de surface/physiologie , Apoptose/effets des médicaments et des substances chimiques , Cardiotoxicité/physiopathologie , Chine , Doxorubicine/pharmacologie , Inflammation/anatomopathologie , Mâle , Glycoprotéines membranaires/génétique , Glycoprotéines membranaires/physiologie , Souris , Souris knockout , Lésion de reperfusion myocardique/métabolisme , Myocarde/anatomopathologie , Facteur de transcription NF-kappa B/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Récepteur de type Toll-4/métabolisme
9.
Oncogene ; 38(48): 7294-7310, 2019 11.
Article de Anglais | MEDLINE | ID: mdl-31427737

RÉSUMÉ

Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced ß-catenin signaling, have more tumor-infiltrating CD103+ dendritic cells and CD8+ T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects ß-catenin from degradation, by interacting with GSK-3ß, which increases ß-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.


Sujet(s)
Antigènes de surface/physiologie , Marqueurs biologiques tumoraux/métabolisme , Colite/complications , Tumeurs colorectales/étiologie , Facteur de croissance épidermique/physiologie , Régulation de l'expression des gènes tumoraux , Mucines/métabolisme , bêta-Caténine/métabolisme , Animaux , Apoptose , Marqueurs biologiques tumoraux/génétique , Carcinogenèse , Prolifération cellulaire , Études de cohortes , Colite/induit chimiquement , Colite/anatomopathologie , Tumeurs colorectales/métabolisme , Tumeurs colorectales/anatomopathologie , Humains , Souris , Souris de lignée C57BL , Souris knockout , Mucines/génétique , Cellules souches tumorales/métabolisme , Cellules souches tumorales/anatomopathologie , Pronostic , Taux de survie , Cellules cancéreuses en culture , bêta-Caténine/génétique
10.
Nat Rev Immunol ; 19(9): 539-549, 2019 09.
Article de Anglais | MEDLINE | ID: mdl-31019284

RÉSUMÉ

Tissue macrophages rapidly recognize and engulf apoptotic cells. These events require the display of so-called eat-me signals on the apoptotic cell surface, the most fundamental of which is phosphatidylserine (PtdSer). Externalization of this phospholipid is catalysed by scramblase enzymes, several of which are activated by caspase cleavage. PtdSer is detected both by macrophage receptors that bind to this phospholipid directly and by receptors that bind to a soluble bridging protein that is independently bound to PtdSer. Prominent among the latter receptors are the MER and AXL receptor tyrosine kinases. Eat-me signals also trigger macrophages to engulf virus-infected or metabolically traumatized, but still living, cells, and this 'murder by phagocytosis' may be a common phenomenon. Finally, the localized presentation of PtdSer and other eat-me signals on delimited cell surface domains may enable the phagocytic pruning of these 'locally dead' domains by macrophages, most notably by microglia of the central nervous system.


Sujet(s)
Apoptose , Macrophages/physiologie , Animaux , Antigènes de surface/physiologie , Humains , Protéines membranaires/physiologie , Protéines de lait , Phagocytose , Phosphatidylsérine/physiologie , Récepteurs à activité tyrosine kinase/physiologie , c-Mer Tyrosine kinase/physiologie
11.
Atherosclerosis ; 284: 11-17, 2019 05.
Article de Anglais | MEDLINE | ID: mdl-30861420

RÉSUMÉ

BACKGROUND AND AIMS: A recently identified locus for coronary artery disease (CAD) tagged by rs8042271 is in a region of tight linkage disequilibrium (LD) between 2 genes (MFGE8, ABHD2) previously linked to atherosclerosis. Here we have explored the regulatory framework of this region to identify its functional relationship to CAD. METHODS: The CAD Associated Region between MFGE8 and ABHD2 (CARMA) was investigated by bioinformatic approaches and transcriptional reporter assays to prioritize target genes and identify putative causal variants. Findings were integrated with publicly available gene expression datasets. MFGE8 silencing was performed in cell models relevant to CAD. RESULTS: The regulatory potential of CARMA is disseminated sparsely over the entire region. CARMA contains multiple eQTL that regulate MFGE8 in coronary artery and coronary artery smooth muscle cell (CoSMC). SNPs that predict the expression of MFGE8 in artery are concordantly associated with higher risk of CAD (pval = 0.0014). Targeting CARMA by CRISPR/Cas9 in a cellular model increased MFGE8 expression. MFGE8 silencing was found to reduce CoSMC and monocyte (THP-1) but not endothelial cell proliferation. CONCLUSIONS: These findings support a mechanistic link between a GWAS identified CAD risk locus and atherosclerosis. The intergenic locus CARMA regulates MFGE8 in a haplotype dependent manner. Individuals genetically susceptible to increased MFGE8 expression exhibit greater CAD risk. Suppressing MFGE8 expression reduced SMC and THP-1 proliferation. These data support an atherogenic contribution of CARMA/MFGE8 that may be linked to cell proliferation and/or improved survival of CAD relevant cell types.


Sujet(s)
Antigènes de surface/génétique , Athérosclérose/génétique , Maladie des artères coronaires/génétique , ADN intergénique/physiologie , Protéines de lait/génétique , Antigènes de surface/physiologie , Régulation de l'expression des gènes , Humains
12.
Birth Defects Res ; 110(14): 1129-1138, 2018 08 15.
Article de Anglais | MEDLINE | ID: mdl-30120883

RÉSUMÉ

BACKGROUND: Worldwide, Neural tube defects (NTDs) are considered as major clinical problems imposing a huge socio-economic burden for both affected individuals and their families. In India, the prevalence of Neural tube defects is significantly high. This study aims to evaluate the association between genetic defects in folate metabolism pathway genes, mainly: Folate hydrolase 1 (FOLH1), Dihydrofolate reductase (DHFR) and Methylenetetrahydrofolate reductase (MTHFR) and neural tube defects from eastern India. METHODS: We enrolled 62 consecutive mothers with NTDs foetuses as cases and their corresponding age matched 73 mothers with healthy babies as controls (genetic power has been calculated). Four single nucleotide polymorphisms (FOLH1: rs202676, DHFR: rs70991108, MTHFR: rs1801133 and rs1801131) have been amplified by polymerase chain reaction (PCR) and sequenced. Statistical analysis has been undertaken to find out association with NTDs. RESULTS: Genotype and allele frequency analysis of these SNPs revealed that, rs1801133 (p.Ala222Val) was significantly associated with NTDs risk (p value = 0.028; odds ratio-2.31; 95% CI 1.08-4.93), whereas rs202676 (p.Tyr60His) showed protective role (p value = 0.0066; odds ratio-0.11; 95% CI 0.01-0.86). Serum homocysteine (Hcy) concentration was respectively higher in subjects carrying 222Ala/Val and 222Val/Val alleles (p value = 0.009; p value ≤ 0.0001). CONCLUSION: In conclusion, it can be stated that, rs1801133 was associated with neural tube defects risk in patients from the eastern part of India and it might be counted as a molecular marker for evaluating the susceptibility of NTDs.


Sujet(s)
Acide folique/génétique , Acide folique/métabolisme , Anomalies du tube neural/génétique , Adulte , Allèles , Antigènes de surface/génétique , Antigènes de surface/physiologie , Études cas-témoins , Femelle , Fréquence d'allèle/génétique , Prédisposition génétique à une maladie/génétique , Génotype , Glutamate carboxypeptidase II/génétique , Glutamate carboxypeptidase II/physiologie , Homocystéine/analyse , Homocystéine/sang , Humains , Inde/épidémiologie , Methylenetetrahydrofolate reductase (NADPH2)/génétique , Methylenetetrahydrofolate reductase (NADPH2)/physiologie , Adulte d'âge moyen , Anomalies du tube neural/épidémiologie , Anomalies du tube neural/physiopathologie , Odds ratio , Polymorphisme de nucléotide simple/génétique , Facteurs de risque , Dihydrofolate reductase/génétique , Dihydrofolate reductase/physiologie
13.
Proc Natl Acad Sci U S A ; 115(16): 4246-4251, 2018 04 17.
Article de Anglais | MEDLINE | ID: mdl-29610346

RÉSUMÉ

Flaviviruses enter host cells through the process of clathrin-mediated endocytosis, and the spectrum of host factors required for this process are incompletely understood. Here we found that lymphocyte antigen 6 locus E (LY6E) promotes the internalization of multiple flaviviruses, including West Nile virus, Zika virus, and dengue virus. Perhaps surprisingly, LY6E is dispensable for the internalization of the endogenous cargo transferrin, which is also dependent on clathrin-mediated endocytosis for uptake. Since viruses are substantially larger than transferrin, we reasoned that LY6E may be required for uptake of larger cargoes and tested this using transferrin-coated beads of similar size as flaviviruses. LY6E was indeed required for the internalization of transferrin-coated beads, suggesting that LY6E is selectively required for large cargo. Cell biological studies found that LY6E forms tubules upon viral infection and bead internalization, and we found that tubule formation was dependent on RNASEK, which is also required for flavivirus internalization, but not transferrin uptake. Indeed, we found that RNASEK is also required for the internalization of transferrin-coated beads, suggesting it functions upstream of LY6E. These LY6E tubules resembled microtubules, and we found that microtubule assembly was required for their formation and flavivirus uptake. Since microtubule end-binding proteins link microtubules to downstream activities, we screened the three end-binding proteins and found that EB3 promotes virus uptake and LY6E tubularization. Taken together, these results highlight a specialized pathway required for the uptake of large clathrin-dependent endocytosis cargoes, including flaviviruses.


Sujet(s)
Flavivirus/physiologie , Pénétration virale , Antigènes de surface/génétique , Antigènes de surface/physiologie , Lignée cellulaire tumorale , Virus de la dengue/physiologie , Endocytose/effets des médicaments et des substances chimiques , Endocytose/physiologie , Endoribonucleases/physiologie , Éthers/pharmacologie , Protéines liées au GPI/déficit , Protéines liées au GPI/génétique , Protéines liées au GPI/physiologie , Techniques de knock-down de gènes , Humains , Microsphères , Protéines associées aux microtubules/physiologie , Microtubules/effets des médicaments et des substances chimiques , Microtubules/physiologie , Nocodazole/pharmacologie , Spiranes/pharmacologie , Transferrine , Virus du Nil occidental/physiologie , Virus Zika/physiologie
14.
Pharmacol Ther ; 188: 12-25, 2018 08.
Article de Anglais | MEDLINE | ID: mdl-29444453

RÉSUMÉ

Atherosclerosis is a dynamic and progressive inflammatory process in the intimal layer of large and medium-sized arteries, and it is the major contributor to the atherosclerotic cardiovascular disease (ACVD), the leading cause of death worldwide. In an atherosclerotic plaque, phagocytosis of apoptotic cells occurs through an intricate process designated efferocytosis. Defective efferocytosis has emerged as a causal factor in the etiopathogenesis of atherosclerosis and its progression into overt ACVD. Both specialized phagocytes (macrophages and dendritic cells) and non-specialized cells with phagocytic capabilities (smooth muscle and endothelial cells) are involved in the efferocytotic process. Moreover, several signaling and regulatory molecules are involved in the different steps of efferocytosis, and they include "Find-Me" signals (lysophosphatidylcholine), "Eat-Me" signals [phosphatidylserine, Mer tyrosine kinase (MerTK), and milk fat globule-EGF factor 8], and "Don't Eat-Me" signals [cluster of differentiation 47 (CD47)]. Regulation of efferocytosis is in a close nexus with inflammation, the key component in atherosclerosis. The predominance of pro-inflammatory and anti-inflammatory molecules plays a crucial role in lesion progression and regression, respectively. Polarization of macrophages towards the M1 phenotype causes them to secrete proinflammatory cytokines, while polarization towards the M2 phenotype causes them to secrete of anti-inflammatory cytokines, including interleukin-10 and transforming growth factor ß, so tending to shift the balance towards resolution of the inflammation. Dysfunction of any regulatory signal may cause expansion of the necrotic core of an atherosclerotic plaque with ensuing conversion of the plaque into an unstable plaque with an increased susceptibility to rupture and to atherothrombotic complication. In this review we aim at elucidating the determinant factors and pathways of efferocytosis which can be considered as potential novel targets when striving to develop more personalized and efficient treatment regimens for patients with ACVD.


Sujet(s)
Athérosclérose/étiologie , Phagocytose/physiologie , Antigènes de surface/physiologie , Apoptose , Antigènes CD47/physiologie , Calréticuline/physiologie , Humains , Protéine-1 apparentée au récepteur des LDL/physiologie , Macrophages/physiologie , Protéines de lait , c-Mer Tyrosine kinase/physiologie
15.
J Immunol ; 199(12): 4023-4035, 2017 12 15.
Article de Anglais | MEDLINE | ID: mdl-29101312

RÉSUMÉ

Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R. Similarly, establishing a multicellular three-dimensional model of human oral mucosa with induced inflammation promoted MMP12 production and reduced CD200R surface expression by monocyte-derived cells. MMP12 production by monocyte-derived cells was induced by CSF2 rather than the cyclooxygenase-2 pathway, and treatment of monocyte-derived cells with a CD200R ligand reduced CSF2-induced MMP12 production. Further, MMP12-mediated degradation of the extracellular matrix proteins tropoelastin and fibronectin in the tissue model coincided with a loss of Ki-67, a protein strictly associated with cell proliferation. Reduced amounts of tropoelastin were confirmed in gingival tissue from PD patients. Thus, this novel association of the CD200/CD200R pathway with MMP12 production by monocyte-derived cells may play a key role in PD progression and will be important to take into consideration in the development of future strategies to diagnose, treat, and prevent PD.


Sujet(s)
Antigènes de surface/physiologie , Gencive/enzymologie , Matrix metalloproteinase 12/physiologie , Monocytes/enzymologie , Parodontite/enzymologie , Récepteurs de surface cellulaire/physiologie , Adulte , Antigènes de surface/biosynthèse , Antigènes de surface/génétique , Division cellulaire , Cellules cultivées , Techniques de coculture , Inhibiteurs des cyclooxygénases/pharmacologie , Cellules épithéliales/métabolisme , Fibroblastes/métabolisme , Cytométrie en flux , Régulation de l'expression des gènes , Gencive/anatomopathologie , Facteur de stimulation des colonies de granulocytes et de macrophages/pharmacologie , Humains , Inflammation , Kératinocytes/métabolisme , Matrix metalloproteinase 12/biosynthèse , Matrix metalloproteinase 12/génétique , Monocytes/anatomopathologie , Récepteurs des orexines , Parodontite/anatomopathologie , Pyrazoles/pharmacologie , Réaction de polymérisation en chaine en temps réel , Récepteurs de surface cellulaire/biosynthèse , Récepteurs de surface cellulaire/génétique
16.
J Am Soc Nephrol ; 28(11): 3262-3277, 2017 Nov.
Article de Anglais | MEDLINE | ID: mdl-28814510

RÉSUMÉ

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia. Immunofluorescence analyses revealed granular antigen-antibody complexes in a subepithelial location along the glomerular filtration barrier 14 days after antibody injection, and immunohistochemistry for rabbit IgG and THSD7A as well as ultrastructural analyses showed the typical characteristics of human MN. Mice injected with purified IgG from rabbit serum that was taken before immunization failed to develop any of these changes. Notably, MN developed in the absence of detectable complement activation, and disease was strain dependent. In vitro, anti-THSD7A antibodies caused cytoskeletal rearrangement and activation of focal adhesion signaling. Knockdown of the THSD7A ortholog, thsd7aa, in zebrafish larvae resulted in altered podocyte differentiation and impaired glomerular filtration barrier function, with development of pericardial edema, suggesting an important role of THSD7A in glomerular filtration barrier integrity. In summary, our study introduces a heterologous mouse model that allows further investigation of the molecular events that underlie MN.


Sujet(s)
Anticorps/physiologie , Antigènes de surface/immunologie , Glomérulonéphrite extra-membraneuse/immunologie , Protéines membranaires/immunologie , Thrombospondines/immunologie , Animaux , Antigènes de surface/physiologie , Modèles animaux de maladie humaine , Humains , Mâle , Protéines membranaires/physiologie , Souris , Souris de lignée BALB C , Lapins , Rats , Rat Sprague-Dawley , Thrombospondines/physiologie
17.
Arch Oral Biol ; 82: 293-301, 2017 Oct.
Article de Anglais | MEDLINE | ID: mdl-28686984

RÉSUMÉ

Mesenchymal stem cells derived from the human tooth germ (hTGSCs) are a heterogeneous cell population that can differentiate into osteogenic, neurogenic, and adipogenic lineages. The aim of this study was to compare the osteogenic differentiation capacity of STRO-1 positive (STRO-1+) hTGSCs and unsorted heterogeneous hTGSCs and to establish if STRO-1+ cells are more committed to osteogenic differentiation. HTGSCs were isolated from impacted third molar tooth germ tissues of adolescents, and a subpopulation of STRO-1+ hTGSCs was obtained by fluorescence-activated cell sorting. STRO-1+, STRO-1 negative (STRO-1-), and unsorted cells were cultured in osteogenic and standard culture media to compare their capacity to differentiate towards osteoblastic lineage. Cells were tested for proliferation rates, alkaline phosphatase activity, and amounts of accumulated calcium. Gene expression levels of the RUNX2, osteocalcin, and osteonectin genes were analyzed with real time PCR. Mineralization and osteogenic protein expression were examined by using von Kossa staining and confocal microscopy. Our results indicated that osteogenically induced cell populations showed greater mineralization capacity than non-induced cells. However, expression levels of early and late osteogenic markers were not significantly different between STRO-1+ and unsorted cells. In conclusion, the selection by STRO-1 expression does not yield cells with osteogenic capacity higher than that of the heterogeneous hTGSC population. Cell sorting using osteogenic markers other than STRO-1 might be beneficial in obtaining a more sensitive osteogenic sub-population from unsorted heterogenous hTGSCs.


Sujet(s)
Antigènes de surface/physiologie , Cellules souches mésenchymateuses/cytologie , Ostéogenèse/physiologie , Germe dentaire/cytologie , Adolescent , Phosphatase alcaline/analyse , Calcium/analyse , Différenciation cellulaire , Prolifération cellulaire , Cellules cultivées , Femelle , Cytométrie en flux , Humains , Mâle , Microscopie confocale , Dent de sagesse , Réaction de polymérisation en chaine en temps réel , Jeune adulte
18.
Braz Oral Res ; 31: e53, 2017 Jul 03.
Article de Anglais | MEDLINE | ID: mdl-28678972

RÉSUMÉ

Peripheral ossifying fibroma (POF) is a reactive lesion of oral tissues, associated with local factors such as trauma or presence of dental biofilm. POF treatment consists of curettage of the lesion combined with root scaling of adjacent teeth and/or removal of other sources of irritants. This study aimed to analyze the clinical and pathological features of POF and to investigate the immunoexpression of Osterix and STRO-1 proteins. Data such as age, gender, and size were obtained from 30 cases of POF. Microscopic features were assessed by conventional light microscopy using hematoxylin-eosin staining and immunohistochemical markers, and by polarized light microscopy using Picrosirius red staining. The age range was 11-70 years and 70% of the patients were female. Moreover, the size of POF varied from 0.2 to 5.0 cm; in 43.33% of the cases, the mineralized content consisted exclusively of bony trabeculae. The immunohistochemical analysis showed nuclear staining for Osterix in 63% and for STRO-1 in 20% of the cases. Mature collagen fibers were observed in mineralized tissue in 76.67% of the cases. The clinical and microscopic features observed were in agreement with those described in the literature. Osterix was overexpressed, while STRO-1 was poorly expressed. Osterix was expressed particularly in cells entrapped in and around mineralized tissue, indicating the presence of a stimulus that triggers the differentiation of these cells into osteoblasts or cementoblasts, i.e., cells that produce mineralized tissue. Based on our results, Osterix may play a role in the pathogenesis of POF.


Sujet(s)
Antigènes de surface/physiologie , Tumeurs osseuses/anatomopathologie , Fibrome ossifiant/anatomopathologie , Facteurs de transcription/physiologie , Adolescent , Adulte , Sujet âgé , Antigènes de surface/analyse , Différenciation cellulaire , Enfant , Collagène/analyse , Femelle , Gencive/anatomopathologie , Humains , Immunohistochimie , Mâle , Microscopie en lumière polarisée , Adulte d'âge moyen , Ostéoblastes/anatomopathologie , Facteur de transcription Sp7 , Facteurs de transcription/analyse , Jeune adulte
19.
BMB Rep ; 50(2): 58-59, 2017 Feb.
Article de Anglais | MEDLINE | ID: mdl-28115038

RÉSUMÉ

The beneficial paracrine roles of mesenchymal stem cells (MSCs) in tissue repair have potential in therapeutic strategies against various diseases. However, the key therapeutic factors secreted from MSCs and their exact molecular mechanisms of action remain unclear. In this study, the cell-free secretome of umbilical cord-derived MSCs showed significant anti-fibrotic activity in the mouse models of liver fibrosis. The involved action mechanism was the regulation of hepatic stellate cell activation by direct inhibition of the TGFß/Smad-signaling. Antagonizing the milk fat globule-EGF factor 8 (MFGE8) activity blocked the anti-fibrotic effects of the MSC secretome in vitro and in vivo. Moreover, MFGE8 was secreted by MSCs from the umbilical cord as well as other tissues, including teeth and bone marrow. Administration of recombinant MFGE8 protein alone had a significant anti-fibrotic effect in two different models of liver fibrosis. Additionally, MFGE8 downregulated TGFß type I receptor expression by binding to αvß3 integrin on HSCs. These findings revealed the potential role of MFGE8 in modulating TGFß-signaling. Thus, MFGE8 could serve as a novel therapeutic agent for liver fibrosis. [BMB Reports 2017; 50(2): 58-59].


Sujet(s)
Antigènes de surface/isolement et purification , Antigènes de surface/physiologie , Cirrhose du foie/prévention et contrôle , Cellules souches mésenchymateuses/métabolisme , Protéines de lait/isolement et purification , Protéines de lait/métabolisme , Animaux , Cellules cultivées , Humains , Cirrhose du foie/métabolisme , Cirrhose du foie/anatomopathologie , Transplantation de cellules souches mésenchymateuses , Métabolome/physiologie , Souris
20.
Braz. oral res. (Online) ; 31: e53, 2017. tab, graf
Article de Anglais | LILACS | ID: biblio-952104

RÉSUMÉ

Abstract Peripheral ossifying fibroma (POF) is a reactive lesion of oral tissues, associated with local factors such as trauma or presence of dental biofilm. POF treatment consists of curettage of the lesion combined with root scaling of adjacent teeth and/or removal of other sources of irritants. This study aimed to analyze the clinical and pathological features of POF and to investigate the immunoexpression of Osterix and STRO-1 proteins. Data such as age, gender, and size were obtained from 30 cases of POF. Microscopic features were assessed by conventional light microscopy using hematoxylin-eosin staining and immunohistochemical markers, and by polarized light microscopy using Picrosirius red staining. The age range was 11-70 years and 70% of the patients were female. Moreover, the size of POF varied from 0.2 to 5.0 cm; in 43.33% of the cases, the mineralized content consisted exclusively of bony trabeculae. The immunohistochemical analysis showed nuclear staining for Osterix in 63% and for STRO-1 in 20% of the cases. Mature collagen fibers were observed in mineralized tissue in 76.67% of the cases. The clinical and microscopic features observed were in agreement with those described in the literature. Osterix was overexpressed, while STRO-1 was poorly expressed. Osterix was expressed particularly in cells entrapped in and around mineralized tissue, indicating the presence of a stimulus that triggers the differentiation of these cells into osteoblasts or cementoblasts, i.e., cells that produce mineralized tissue. Based on our results, Osterix may play a role in the pathogenesis of POF.


Sujet(s)
Humains , Mâle , Femelle , Enfant , Adolescent , Adulte , Sujet âgé , Jeune adulte , Facteurs de transcription/physiologie , Tumeurs osseuses/anatomopathologie , Fibrome ossifiant/anatomopathologie , Antigènes de surface/physiologie , Ostéoblastes/anatomopathologie , Facteurs de transcription/analyse , Immunohistochimie , Différenciation cellulaire , Collagène/analyse , Facteur de transcription Sp7 , Gencive/anatomopathologie , Microscopie en lumière polarisée , Adulte d'âge moyen , Antigènes de surface/analyse
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