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1.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064584

RESUMO

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased ß1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.


Assuntos
Regulação da Expressão Gênica , Cirrose Hepática/patologia , Fator de Crescimento Neural/metabolismo , Polissacarídeos/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Estresse Fisiológico , Tioacetamida/toxicidade , Animais , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/genética
2.
Proc Natl Acad Sci U S A ; 110(28): 11451-6, 2013 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-23798433

RESUMO

Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1-mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.


Assuntos
Galectina 1/fisiologia , Neovascularização Fisiológica/fisiologia , Pré-Eclâmpsia/etiologia , Animais , Modelos Animais de Doenças , Feminino , Galectina 1/metabolismo , Humanos , Camundongos , Placenta/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Trofoblastos/citologia
3.
Glycobiology ; 25(8): 825-35, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25882295

RESUMO

Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a preneoplastic condition for hepatocellular carcinoma (HCC). 4-Methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anticancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumor microenvironment. Hepa129 tumor cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (vascular endothelial growth factor, VEGF, interleukin-6, IL-6 and C-X-C motif chemokine 12, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumor growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumor tissue and in nontumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumor activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Himecromona/farmacologia , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Administração Oral , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Transdução de Sinais , Análise de Sobrevida , Tioacetamida , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Angiogenesis ; 17(1): 119-28, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24068342

RESUMO

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.


Assuntos
Células Dendríticas/metabolismo , Cirrose Hepática/metabolismo , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígeno CD11c/biossíntese , Antígeno CD11c/genética , Células Dendríticas/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Camundongos , Camundongos Transgênicos , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
5.
Immunol Cell Biol ; 92(10): 851-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25155466

RESUMO

Follicular dendritic cells (FDCs) present antigens to B cells in the lymphoid follicle and inhibit B-cell apoptosis. In previous work, we obtained human FDC lines that allowed us to study the antigen phenotype and functions of these cells, finding that they expressed α-smooth muscle (SM) actin (a protein involved in cell contraction) and were able to contract collagen gel matrixes in gel contraction assays. Actin polymerization associated with cell contractility is essential for many cellular functions. We report here that interleukin (IL)-2 and interferon (IFN)-γ increased FDC contractility, and IL-10 reduced contractility, whereas IL-4 had no effect. Tumor necrosis factor (TNF) and lymphotoxin (LT)-α1ß2, cytokines involved in FDC differentiation, also increased FDC contractility. In different cell systems, cell contraction is related with the incorporation of α-SM actin into stress fibers. By confocal microscopy, we showed that cytochalasin D, an inhibitor of actin polymerization, inhibited α-SM actin incorporation and relaxed FDCs. Likewise, IL-10 significantly decreased the proportion of FDCs with α-SM actin-positive stress fibers, whereas cytokines that increased FDC contractility also increased this proportion. However, none of the cytokines tested significantly affected α-SM actin expression as determined by flow cytometry. IL-10, in addition to decreasing FDC contractility, increased the inhibitory activity of FDC in spontaneous B-cell apoptosis (P<0.05), but the other cytokines did not affect this activity. We conclude that cytokines related with FDC physiology regulate the contractility of these cells, and IL-10 also regulates the effect of FDC on B-cell apoptosis.


Assuntos
Actinas/metabolismo , Apoptose/fisiologia , Linfócitos B/imunologia , Citocinas/farmacologia , Células Dendríticas Foliculares/fisiologia , Diferenciação Celular , Células Cultivadas , Células Dendríticas Foliculares/efeitos dos fármacos , Humanos
6.
Mol Hum Reprod ; 20(7): 644-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24637109

RESUMO

Galectin-1 (gal-1) is a prototype carbohydrate-binding protein, whose dysregulation is associated with adverse pregnancy outcomes such as spontaneous abortion and pre-eclampsia. Furthermore, it is known that faulty gal-1 protein production or gene regulation can be caused by single-nucleotide polymorphisms in the LGALS1 gene. Gestational diabetes mellitus (GDM) is also an adverse pregnancy outcome and the most common metabolic disorder during gestation. However, gal-1 expression patterns during GDM remain largely unknown. Our aims were to define local and peripheral gal-1 expression patterns during pregnancy, and to investigate LGALS1 gene polymorphisms in GDM patients. Circulating gal-1 levels were determined by ELISA in GDM patients and normal pregnant controls, and LGALS1 gene polymorphisms were assessed for association with GDM. Placental tissues were collected from control and GDM term pregnancies to evaluate local gal-1 expression by immunofluorescence. Our results show that GDM is associated with a failure to increase circulating gal-1 levels during the second and third trimester, as well as overexpression of gal-1 in placental tissue. Additionally, the LGALS1 polymorphism rs4820294 was associated with the development of GDM. In pregnancies complicated by GDM, we observed gal-1 dysregulation both locally in the placenta and peripherally in the circulation. Furthermore, the association between the LGALS1 polymorphism and GDM may indicate a genetic contribution to this adverse pregnancy outcome.


Assuntos
Diabetes Gestacional/metabolismo , Galectina 1/metabolismo , Placenta/metabolismo , Diabetes Gestacional/genética , Feminino , Galectina 1/genética , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez
7.
Reproduction ; 148(2): 179-89, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24825909

RESUMO

Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of the decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the establishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, in this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further boosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through recruitment of NGF-expressing immune cells, increased decidual innervation with substance P(+) nerve fibres and a Th1 cytokine shift. Similarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions associated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the models, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development. We further demonstrated that spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. Thus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed may result in fetal rejection due to exacerbated inflammation.


Assuntos
Aborto Espontâneo/etiologia , Aborto Espontâneo/metabolismo , Decídua/metabolismo , Embrião de Mamíferos/metabolismo , Fator de Crescimento Neural/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo , Aborto Espontâneo/patologia , Animais , Western Blotting , Células Cultivadas , Decídua/citologia , Embrião de Mamíferos/citologia , Feminino , Reabsorção do Feto/etiologia , Reabsorção do Feto/metabolismo , Reabsorção do Feto/patologia , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Fator de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Placenta/citologia , Gravidez , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trofoblastos/citologia
8.
Angiogenesis ; 16(2): 417-27, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23224220

RESUMO

Early pregnancy is characterized by decidual adaption to the developing embryo involving angiogenesis and vascular growth. Failure of decidual vascular expansion is linked to diseases of pregnancy. Dendritic cells (DC) have been associated with vascular growth during early gestation, though it is unknown whether their capacity to modulate angiogenesis is ubiquitous to all DC subsets. Here, we show that DC normally found associated with the decidual vasculature co-express the C-X-C chemokine receptor type 4 (CXCR4). In addition, we demonstrate that impaired homing of CXCR4(+)DC during early gestation provoked a disorganized decidual vasculature with impaired spiral artery remodeling later in gestation. In contrast, adoptive transfer experiments provided evidence that CXCR4(+)DC are able to rescue early pregnancy by normalizing decidual vascular growth and delivery of pro-angiogenic factors, which results in adequate remodeling of the spiral arteries during placental development. Taken together, our results indicate an important role of CXCR4(+)DC in the regulation of decidual angiogenesis and highlight the importance of the CXCL12/CXCR4 pathway during this process, suggesting that this may represent a key pathway to evaluate during pregnancy pathologies associated with impaired vascular expansion.


Assuntos
Células Dendríticas/imunologia , Implantação do Embrião , Neovascularização Patológica , Receptores CXCR4/fisiologia , Animais , Sequência de Bases , Primers do DNA , Camundongos , Reação em Cadeia da Polimerase
9.
Biol Reprod ; 88(1): 22, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23242525

RESUMO

Disruption of fetal-maternal tolerance mechanisms can contribute to pregnancy complications, including spontaneous abortion. Galectin-9 (LGALS9), a tandem repeat lectin associated with immune modulation, is expressed in the endometrium during the mid and late secretory phases and in decidua during human early pregnancy. However, the role of LGALS9 during pregnancy remains poorly understood. We used real-time PCR and immunohistochemical staining to analyze the expression of Lgals9/LGALS9 during mouse gestation as well as in human tissues obtained from normal pregnancy and spontaneous abortions. In mice, three Lgals9 splice variants were detected, the expression of which was differentially regulated during gestation. Furthermore, decidual Lgals9 expression was deregulated in a mouse model of spontaneous abortion, whereas placental levels did not change. We further found that the LGALS9 D5 isoform suppresses interferon gamma production by decidual natural killer cells. In human patients, six Lgals9 splice variants were detected, and a decrease in Lgals9 D5/10 was associated with spontaneous abortion. Altogether, these results show a differential regulation of Lgals9 isoform expression during normal and pathological pregnancies and designate Lgals9 as a potential marker for adverse pregnancy outcomes.


Assuntos
Aborto Espontâneo/metabolismo , Galectinas/metabolismo , Regulação da Expressão Gênica/fisiologia , Relações Materno-Fetais/fisiologia , Animais , Biomarcadores , Feminino , Galectinas/genética , Humanos , Células Matadoras Naturais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Gravidez , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
10.
Mol Hum Reprod ; 19(1): 43-53, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23002109

RESUMO

Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLA-G) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation.


Assuntos
Aborto Espontâneo/imunologia , Decídua/imunologia , Galectina 1/imunologia , Antígenos HLA-G/imunologia , Placenta/imunologia , Trofoblastos/imunologia , Aborto Espontâneo/sangue , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/genética , Adulto , Biomarcadores/sangue , Blastocisto/imunologia , Adesão Celular/imunologia , Linhagem Celular , Decídua/metabolismo , Implantação do Embrião/imunologia , Feminino , Galectina 1/sangue , Galectina 1/genética , Expressão Gênica/imunologia , Antígenos HLA-G/sangue , Antígenos HLA-G/genética , Humanos , Evasão da Resposta Imune , Tolerância Imunológica , Isoantígenos/imunologia , Placenta/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Prognóstico , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Trofoblastos/metabolismo
11.
Biol Reprod ; 86(6): 191, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22423048

RESUMO

Mouse and human pregnancy-specific glycoproteins (PSG) are known to exert immunomodulatory functions during pregnancy by inducing maternal leukocytes to secrete anti-inflammatory cytokines that promote a tolerogenic decidual microenvironment. Many such anti-inflammatory mediators also function as proangiogenic factors, which, along with the reported association of murine PSG with the uterine vasculature, suggest that PSG may contribute to the vascular adaptations necessary for successful implantation and placental development. We observed that PSG22 is strongly expressed around the embryonic crypt on Gestation Day 5.5, indicating that trophoblast giant cells are the main source of PSG22 during the early stages of pregnancy. PSG22 treatment up-regulated the secretion of transforming growth factor beta 1 and vascular endothelial growth factor A (VEGFA) in murine macrophages, uterine dendritic cells, and natural killer cells. A possible role of PSGs in uteroplacental angiogenesis is further supported by the finding that incubation of endothelial cells with PSG22 resulted in the formation of tubes in the presence and absence of VEGFA. We determined that PSG22, like human PSG1 and murine PSG17 and PSG23, binds to the heparan sulfate chains in syndecans. Therefore, our findings indicate that despite the independent evolution and expansion of human and rodent PSG, members in both families have conserved functions that include their ability to induce anti-inflammatory cytokines and proangiogenic factors as well as to induce the formation of capillary structures by endothelial cells. In summary, our results indicate that PSG22, the most abundant PSG expressed during mouse early pregnancy, is likely a major contributor to the establishment of a successful pregnancy.


Assuntos
Glicoproteínas/metabolismo , Neovascularização Fisiológica , Proteínas da Gravidez/metabolismo , Prenhez/metabolismo , Trofoblastos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Células Dendríticas/metabolismo , Feminino , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Gravidez , Prenhez/imunologia , Proteínas Recombinantes/metabolismo , Sindecanas/metabolismo , Tetraspanina 29/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Clin Immunol ; 139(1): 48-56, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21292557

RESUMO

The purpose of this study was to determine whether the proportion of galectin-1-expressing peripheral blood T and NK cells is altered in normal pregnancy and preeclampsia (PE). We also examined whether circulating levels of galectin-1 and anti-galectin-1 autoantibodies are affected in PE. Seventy preeclamptic patients, 75 healthy pregnant and 21 healthy non-pregnant women were involved in this study. Serum galectin-1 and anti-galectin-1 autoantibody levels were measured by ELISA. Intracellular galectin-1 expression of lymphocytes was determined with flow cytometry. Serum galectin-1 and anti-galectin-1 IgG levels did not differ significantly between the healthy pregnant and the PE group. In healthy pregnant women, significantly higher percentage of T and NK cells expressed gal-1 in their cytoplasma than in healthy non-pregnant women. However, the proportion of galectin-1-expressing peripheral blood T and NK cells was markedly decreased in PE compared to normal pregnancy, which might contribute to the activation of innate and acquired immune cells.


Assuntos
Galectina 1/metabolismo , Regulação da Expressão Gênica/fisiologia , Células Matadoras Naturais/metabolismo , Pré-Eclâmpsia/metabolismo , Linfócitos T/metabolismo , Adulto , Autoanticorpos , Feminino , Galectina 1/genética , Galectina 1/imunologia , Humanos , Gravidez
13.
Cancer Discov ; 11(11): 2924-2943, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34103328

RESUMO

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell- and T cell-dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1-refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659.


Assuntos
Leucemia , Humanos , Imunoterapia , Leucemia/terapia , Macrófagos , Transdução de Sinais
14.
Front Immunol ; 11: 1316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760395

RESUMO

Immune cells [e. g., dendritic cells (DC) and natural killer (NK) cells] are critical players during the pre-placentation stage for successful mammalian pregnancy. Proper placental and fetal development relies on balanced DC-NK cell interactions regulating immune cell homing, maternal vascular expansion, and trophoblast functions. Previously, we showed that in vivo disruption of the uterine NK cell-DC balance interferes with the decidualization process, with subsequent impact on placental and fetal development leading to fetal growth restriction. Glycans are essential determinants of reproductive health and the glycocode expressed in a particular compartment (e.g., placenta) is highly dependent on the cell type and its developmental and pathological state. Here, we aimed to investigate the maternal and placental glycovariation during the pre- and post-placentation period associated with disruption of the NK cell-DC dynamics during early pregnancy. We observed that depletion of NK cells was associated with significant increases of O- and N-linked glycosylation and sialylation in the decidual vascular zone during the pre-placental period, followed by downregulation of core 1 and poly-LacNAc extended O-glycans and increased expression of branched N-glycans affecting mainly the placental giant cells and spongiotrophoblasts of the junctional zone. On the other hand, expansion of DC induced a milder increase of Tn antigen (truncated form of mucin-type O-glycans) and branched N-glycan expression in the vascular zone, with only modest changes in the glycosylation pattern during the post-placentation period. In both groups, this spatiotemporal variation in the glycosylation pattern of the implantation site was accompanied by corresponding changes in galectin-1 expression. Our results show that pre- and post- placentation implantation sites have a differential glycopattern upon disruption of the NK cell-DC dynamics, suggesting that immune imbalance early in gestation impacts placentation and fetal development by directly influencing the placental glycocode.


Assuntos
Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Placenta/imunologia , Placentação , Animais , Feminino , Glicosilação , Masculino , Camundongos Endogâmicos BALB C , Gravidez
15.
Am J Reprod Immunol ; 84(6): e13311, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32691950

RESUMO

PROBLEM: From conception, a delicate regulation of galectins, a family of carbohydrate-binding proteins, is established to ensure maternal immune tolerance in pregnancy. Though galectin-3 (gal-3), the only chimera-type galectin, is abundantly expressed at the feto-maternal interface; the physiological role of this lectin during pregnancy remains to be fully elucidated and requires further investigation. METHOD OF STUDY: In this study, we analyzed serum gal-3 levels during the course of healthy gestation. Trophoblast functions were evaluated upon gal-3 exogenous stimulation using trophoblastic cell lines (e.g. , HIPEC65, SGHPL-4, and BeWo cells). Finally, we investigated variations in peripheral gal-3 levels associated with the development of spontaneous abortion and gestational diabetes mellitus (GDM). RESULTS: Gal-3 circulating levels increased as normal pregnancy progressed. In vitro experiments showed that exogenous gal-3 positively regulated trophoblast functions inducing invasion, tube formation, and fusion. Compared with normal pregnant women, circulating gal-3 levels were significantly decreased in patients who developed GDM. CONCLUSION: Our results reveal a physiological role for gal-3 during pregnancy, promoting proper trophoblast functions associated with healthy gestation. GDM is associated with a failure to increase circulating gal-3 levels late in gestation. Thus, dysregulation of gal-3 may indicate a contribution of the chimera-type lectin to this adverse pregnancy outcome.


Assuntos
Aborto Espontâneo/metabolismo , Diabetes Gestacional/metabolismo , Galectina 3/metabolismo , Gravidez/metabolismo , Trofoblastos/metabolismo , Linhagem Celular , Feminino , Galectina 3/genética , Humanos , Tolerância Imunológica , Circulação Placentária , Trofoblastos/patologia
16.
Cell Death Dis ; 11(7): 560, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703931

RESUMO

Fetal growth restriction (FGR) is the most common pregnancy complication in developed countries. Pregnancies affected by FGR, frequently concur with complications and high risk of neonatal morbidity and mortality. To date, no approved treatment is available for pregnant women affected with FGR. The objective of this study was to investigate the contribution of galectin-3 (gal-3), a ß-galactoside binding protein involved in pregnancy, placental function and fetal growth. We demonstrated that lack of gal-3 during mouse pregnancy leads to placental dysfunction and drives FGR in the absence of a maternal preeclampsia syndrome. Analysis of gal-3 deficient dams revealed placental inflammation and malperfusion, as well as uterine natural killer cell infiltration with aberrant activation. Our results also show that FGR is associated with a failure to increase maternal circulating gal-3 levels during the second and third trimester in human pregnancies. Placentas from human pregnancies affected by FGR displayed lower gal-3 expression, which correlated with placental dysfunction. These data highlight the importance of gal-3 in the promotion of proper placental function, as its absence leads to placental disease and subsequent FGR.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Galectina 3/deficiência , Galectina 3/metabolismo , Insuficiência Placentária/metabolismo , Animais , Feminino , Desenvolvimento Fetal , Humanos , Masculino , Camundongos Endogâmicos C57BL , Placentação , Gravidez , Fatores de Risco
17.
Placenta ; 28(7): 650-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17113145

RESUMO

The materno-fetal interface has for long been considered as an immune privileged biological site and thus understanding the mechanisms underlying fetal survival have been the focus of intense research. In adults, survivin and Stat-3 proteins are involved in tolerance as well as the induction of apoptosis. However, the role of these molecules in pregnancy and development has not been addressed. We have evaluated the expression of survivin and Stat-3 in allogeneic mouse models of low abortions (CBA/J x Balb/c), abortion prone (CBA/J x DBA/2J) and stress-triggered abortions from DBA/2J-mated CBA/J mice. We show that survivin is over-expressed in abortion-prone mating on gestation day 7.5. This effect was also found in stress-exposed mice, whereas expression was low in normal pregnancy mice. The phosphorylated Stat-3 (p-Stat-3) was down regulated in high abortion mating compared with low abortion mating, CBA/J x Balb/c. The level of apoptosis was similar in the three groups studied. Our results suggest that high expression of survivin and low expression of p-Stat-3 are involved in pregnancy loss in mice.


Assuntos
Aborto Espontâneo/metabolismo , Implantação do Embrião , Proteínas Associadas aos Microtúbulos/metabolismo , Placenta/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose , Western Blotting , Decídua/química , Decídua/metabolismo , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos , Proteínas Associadas aos Microtúbulos/análise , Placenta/química , Gravidez , Proteínas Repressoras , Fator de Transcrição STAT3/análise , Survivina , Regulação para Cima
18.
Sci Rep ; 7(1): 2189, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28526846

RESUMO

DC-NK cell interactions are thought to influence the development of maternal tolerance and de novo angiogenesis during early gestation. However, it is unclear which mechanism ensures the cooperative dialogue between DC and NK cells at the feto-maternal interface. In this article, we show that uterine NK cells are the key source of IL-10 that is required to regulate DC phenotype and pregnancy success. Upon in vivo expansion of DC during early gestation, NK cells expressed increased levels of IL-10. Exogenous administration of IL-10 was sufficient to overcome early pregnancy failure in dams treated to achieve simultaneous DC expansion and NK cell depletion. Remarkably, DC expansion in IL-10-/- dams provoked pregnancy loss, which could be abrogated by the adoptive transfer of IL-10+/+ NK cells and not by IL-10-/- NK cells. Furthermore, the IL-10 expressing NK cells markedly enhanced angiogenic responses and placental development in DC expanded IL-10-/- dams. Thus, the capacity of NK cells to secrete IL-10 plays a unique role facilitating the DC-NK cell dialogue during the establishment of a healthy gestation.


Assuntos
Comunicação Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-10/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Troca Materno-Fetal , Aborto Espontâneo/genética , Aborto Espontâneo/metabolismo , Animais , Feminino , Desenvolvimento Fetal/genética , Humanos , Camundongos , Camundongos Knockout , Gravidez , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
20.
Cell Mol Immunol ; 11(5): 449-55, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24954224

RESUMO

A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN(+) dendritic cells (DCs) and CD56(+) natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK-DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua.


Assuntos
Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Útero/imunologia , Antígeno CD56/metabolismo , Moléculas de Adesão Celular/metabolismo , Comunicação Celular , Feminino , Humanos , Tolerância Imunológica , Lectinas Tipo C/metabolismo , Gravidez , Receptores de Superfície Celular/metabolismo
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