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1.
J Immunol ; 198(1): 128-137, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27872212

RESUMEN

Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4+ T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4+ Foxp3+ regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2+ Tregs that also arise in immune-mediated hepatitis.


Asunto(s)
Hepatitis Autoinmune/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Traslado Adoptivo , Animales , Citocinas/biosíntesis , Citocinas/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Interleucina-33/biosíntesis , Interleucina-33/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Linfocitos T Reguladores/inmunología
2.
J Immunol ; 195(8): 3675-84, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26363054

RESUMEN

The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b(-) bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α-induced expression of specific cytokines, such as CXCL5, IL-1ß, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.


Asunto(s)
Células de la Médula Ósea/inmunología , Proteínas Portadoras/inmunología , Diferenciación Celular/inmunología , Células Madre Mesenquimatosas/inmunología , Osteogénesis/inmunología , Animales , Células de la Médula Ósea/patología , Proteínas Portadoras/genética , Diferenciación Celular/genética , Citocinas/genética , Citocinas/inmunología , Dermatitis/genética , Dermatitis/inmunología , Dermatitis/patología , Péptidos y Proteínas de Señalización Intracelular , Células Madre Mesenquimatosas/patología , Ratones , Ratones Mutantes , Osteogénesis/genética
3.
Chembiochem ; 16(14): 2023-8, 2015 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-26296625

RESUMEN

The effect of galectin-mediated microdomain formation on the spatiotemporal dynamics of glycosylated membrane proteins in human microvascular endothelial cells (HMEC-1) was studied qualitatively and quantitatively by high-resolution fluorescence microscopy and artificially mimicked by metabolic glycoprotein engineering. Two types of membrane proteins, sialic acid-bearing proteins (SABPs) and mucin-type proteins (MTPs), were investigated. For visualization they were metabolically labeled with azido sugars and then coupled to a cyclooctyne-conjugated fluorescent dye by click chemistry. Both spatial (diffusion) and temporal (residence time) dynamics of SABPs and MTPs on the membrane were investigated after treatment with exogenous galectin-1 or -3. Strong effects of galectin-mediated lattice formation were observed for MTPs (decreased spatial mobility), but not for SABPs. Lattice formation also strongly decreased the turnover of MTPs (increased residence time on the cell membrane). The effects of galectin-mediated crosslinking was accurately mimicked by streptavidin-mediated crosslinking of biotin-tagged glycoproteins and verified by single-molecule tracking. This technique allows the induction of crosslinking of membrane proteins under precisely controlled conditions, thereby influencing membrane residence time and the spatial dynamics of glycans on the cell membrane in a controlled way.


Asunto(s)
Células Endoteliales/metabolismo , Galectinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Microdominios de Membrana/metabolismo , Línea Celular , Difusión , Células Endoteliales/citología , Humanos , Glicoproteínas de Membrana/análisis , Microdominios de Membrana/ultraestructura , Mucinas/análisis , Mucinas/metabolismo , Ácidos Siálicos/análisis , Ácidos Siálicos/metabolismo
4.
Semin Immunopathol ; 44(4): 445-459, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35122118

RESUMEN

Tumour necrosis factor-α (TNF) is a multifunctional cytokine. First recognized as an endogenous soluble factor that induces necrosis of solid tumours, TNF became increasingly important as pro-inflammatory cytokine being involved in the immunopathogenesis of several autoimmune diseases. In the liver, TNF induces numerous biological responses such as hepatocyte apoptosis and necroptosis, liver inflammation and regeneration, and autoimmunity, but also progression to hepatocellular carcinoma. Considering these multiple functions of TNF in the liver, we propose anti-TNF therapies that specifically target TNF signalling at the level of its specific receptors.


Asunto(s)
Neoplasias Hepáticas , Factor de Necrosis Tumoral alfa , Citocinas , Humanos , Inflamación/patología , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Inhibidores del Factor de Necrosis Tumoral
5.
Blood ; 113(26): 6726-36, 2009 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-19273835

RESUMEN

Local inflammation during cutaneous leishmaniasis is accompanied by accumulation of CD11b(+) cells at the site of the infection. A functional role for these monocytic cells in local angiogenesis in leishmaniasis has not been described so far. Here, we show that CD11b(+) cells express high levels of the myeloid differentiation antigen carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). In experimental cutaneous leishmaniasis in C57BL/6 wild-type (B6.WT) and B6.Ceacam1(-/-) mice, we found that only B6.Ceacam1(-/-) mice develop edemas and exhibit impairment of both hemangiogenesis and lymphangiogenesis. Because CEACAM1 expression correlates with functional angiogenesis, we further analyzed the role of the CD11b(+) population. In B6.Ceacam1(-/-) mice, we found systemic reduction of Ly-6C(high)/CD11b(high) monocyte precursors. To investigate whether CEACAM1(+) myeloid cells are causally related to efficient angiogenesis, we used reverse bone marrow transplants (BMTs) to restore CEACAM1(+) or CEACAM1(-) bone marrow in B6.Ceacam1(-/-) or B6.WT recipients, respectively. We found that angiogenesis was restored by CEACAM1(+) BMT only. In addition, we observed reduced morphogenic potential of inflammatory cells in Matrigel implants in CEACAM1(-) backgrounds or after systemic depletion of CD11b(high) macrophages. Taken together, we show for the first time that CEACAM1(+) myeloid cells are crucial for angiogenesis in inflammation.


Asunto(s)
Antígeno Carcinoembrionario/análisis , Inflamación/fisiopatología , Leishmaniasis Cutánea/fisiopatología , Células Mieloides/fisiología , Neovascularización Patológica/fisiopatología , Animales , Anticuerpos Antiprotozoarios/biosíntesis , Trasplante de Médula Ósea , Antígeno CD11b/análisis , Antígeno Carcinoembrionario/biosíntesis , Antígeno Carcinoembrionario/genética , Colágeno , Combinación de Medicamentos , Edema/etiología , Edema/patología , Glicoproteínas/biosíntesis , Inmunidad Celular , Implantes Experimentales , Inflamación/etiología , Inflamación/inmunología , Interferón gamma/biosíntesis , Laminina , Leishmania major/inmunología , Leishmaniasis Cutánea/complicaciones , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/patología , Vasos Linfáticos/metabolismo , Macrófagos/parasitología , Macrófagos/fisiología , Proteínas de Transporte de Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/química , Células Mieloides/clasificación , Neovascularización Patológica/patología , Proteoglicanos , Quimera por Radiación , Células TH1/inmunología
6.
Chem Commun (Camb) ; 46(2): 330-2, 2010 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-20024368

RESUMEN

A combination of microtiter plate functionalization techniques and two facile bacterial adhesion inhibition assays form a flexible toolbox for the investigation of bacterial adhesion mechanisms on glycosylated surfaces.


Asunto(s)
Adhesión Bacteriana/fisiología , Escherichia coli/fisiología , Glicosilación , Proteínas Fluorescentes Verdes/química , Polisacáridos/química , Juego de Reactivos para Diagnóstico , Propiedades de Superficie
7.
Eur J Cell Biol ; 89(1): 87-94, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20034698

RESUMEN

Members of the family of carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) belonging to the immunoglobulin (Ig) superfamily are expressed in a variety of normal and malignant human tissues. As components of the cell membrane, these glycoproteins can make contact with adjacent cells. CEACAM1 and CEACAM5 (CEA) express Lewis(x) (Le(x)) structures. As shown by mass spectrometry in conjunction with enzymatic digestion, CEACAM1 contains at least seven Le(x) residues. Fucosyltransferase IX is the main fucosyltransferase responsible for attachment of terminal fucose, the key feature of the Le(x) structure, to CEA and CEACAM1. The Le(x) residues of both, CEACAM1 and CEA, interact with the human Le(x)-binding glycan receptors DC-SIGN and SRCL. Since subpopulations of human macrophages express DC-SIGN or SRCL, Le(x)-carrying CEACAMs may modulate the immune response in normal tissues such as the human placenta or in malignant tumours, for example in colorectal, pancreatic or lung carcinomas.


Asunto(s)
Antígenos CD/metabolismo , Antígeno Carcinoembrionario/metabolismo , Moléculas de Adhesión Celular/metabolismo , Colectinas/metabolismo , Lectinas Tipo C/metabolismo , Polisacáridos/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Depuradores/metabolismo , Proteínas Recombinantes/metabolismo , Línea Celular , Neoplasias Colorrectales/metabolismo , Femenino , Fucosa/metabolismo , Fucosiltransferasas/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Antígeno Lewis X/metabolismo , Melanoma/metabolismo , Placenta/metabolismo , Embarazo , Unión Proteica , Neoplasias Cutáneas/metabolismo , Extractos de Tejidos
8.
Glycobiology ; 15(1): 87-100, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15317738

RESUMEN

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on epithelia, blood vessel endothelia, and leukocytes. A variety of physiological functions have been assigned to CEACAM1. It is involved in the formation of glands and blood vessels, in immune reactions, and in the regulation of tumor growth. As a homophilic and heterophilic adhesion receptor, it signals through different cellular pathways. The existence of special oligosaccharide structures such as Lewis x or sialyl-Lewis x glycans within this highly glycosylated protein has been postulated, but chemical proof is missing so far. Because such structures are known to be essential for different cell-cell recognition and adhesion processes, characterizing the CEACAM1 glycan structure is of pivotal importance in revealing the biological function of CEACAM1. We examine the terminal glycosylation pattern of CEACAM1 from human granulocytes, focusing on Lewis x epitopes. Lewis x-specific antibodies react with immunoaffinity-purified native CEACAM1. Antibody binding was completely abolished by treatment with fucosidase III, confirming a terminal alpha(1-3,4) fucose linkage to the N-acetylglucosamine of lactosamine residues, a key feature of Lewis epitopes. To verify these data, MALDI-TOF MS analysis after stepwise exoglycosidase digestion of the CEACAM1 N-glycan mixture was performed. A complex mixture of CEACAM1-bound oligosaccharides could be characterized with an unusually high amount of fucose. The sequential digestions clearly identified several different Lewis x glycan epitopes, which may modulate the cell adhesive functions of CEACAM1.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación/metabolismo , Granulocitos/metabolismo , Oligosacáridos/metabolismo , Anticuerpos/inmunología , Antígenos CD/química , Antígenos CD/aislamiento & purificación , Antígenos de Diferenciación/química , Antígenos de Diferenciación/aislamiento & purificación , Western Blotting , Moléculas de Adhesión Celular , Línea Celular , Glicósido Hidrolasas/metabolismo , Humanos , Monosacáridos/metabolismo , Polisacáridos/química , Polisacáridos/metabolismo , Antígeno Sialil Lewis X , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
9.
Am J Pathol ; 165(5): 1781-7, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15509546

RESUMEN

Expression of the cell adhesion molecule CEACAM1 in melanomas is an independent factor for the risk of metastasis with a predictive value superior to that of tumor thickness. We have previously shown that CEACAM1 co-localizes at the tumor-stroma interface of invading melanoma masses with integrin beta(3) and that these two adhesion molecules interact via the CEACAM1 cytoplasmic domain. To address the functional consequences of CEACAM1 expression, we investigated invasion and migration of melanocytic and melanoma cells that stably express CEACAM1 using two different in vitro systems. Here, we demonstrate that CEACAM1 expression markedly enhances cell invasion and migration. The enhanced invasion and migration of CEACAM1-transfected cells was dependent on the presence of Tyr-488 within the full-length cytoplasmic CEACAM1 domain. Treatment with anti-CEACAM monoclonal antibodies blocked CEACAM1-enhanced cell invasion and cell migration in a dose-dependent manner. Furthermore, the enhanced invasion and migration of CEACAM1-transfected melanoma cells was blocked by integrin-antagonizing RGD peptides. Expression of integrin beta(3) induces the up-regulation of CEACAM1 in melanocytic MEL6 cells. These results strengthen the view that CEACAM1 and alpha(v)beta(3) integrin are functionally interconnected with respect to the invasive growth of melanomas.


Asunto(s)
Antígenos CD/fisiología , Antígenos de Diferenciación/fisiología , Integrina alfaVbeta3/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Anticuerpos Monoclonales/química , Western Blotting , Adhesión Celular , Moléculas de Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Citoplasma/metabolismo , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Integrina beta3/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Oligopéptidos/química , Estructura Terciaria de Proteína , Factores de Tiempo , Transfección , Tirosina/química , Regulación hacia Arriba
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