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1.
Nat Immunol ; 20(12): 1668-1680, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31636464

RESUMEN

Lymph node fibroblastic reticular cells (FRCs) respond to signals from activated T cells by releasing nitric oxide, which inhibits T cell proliferation and restricts the size of the expanding T cell pool. Whether interactions with FRCs also support the function or differentiation of activated CD8+ T cells is not known. Here we report that encounters with FRCs enhanced cytokine production and remodeled chromatin accessibility in newly activated CD8+ T cells via interleukin-6. These epigenetic changes facilitated metabolic reprogramming and amplified the activity of pro-survival pathways through differential transcription factor activity. Accordingly, FRC conditioning significantly enhanced the persistence of virus-specific CD8+ T cells in vivo and augmented their differentiation into tissue-resident memory T cells. Our study demonstrates that FRCs play a role beyond restricting T cell expansion-they can also shape the fate and function of CD8+ T cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Fibroblastos/fisiología , Ganglios Linfáticos/inmunología , Animales , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Reprogramación Celular , Ensamble y Desensamble de Cromatina , Citotoxicidad Inmunológica , Epigénesis Genética , Regulación de la Expresión Génica , Memoria Inmunológica , Interleucina-6/genética , Interleucina-6/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo
2.
J Immunol ; 213(6): 865-875, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39072698

RESUMEN

Chronic inflammasome activation in mononuclear phagocytes (MNPs) promotes fibrosis in various tissues, including the kidney. The cellular and molecular links between the inflammasome and fibrosis are unclear. To address this question, we fed mice lacking various immunological mediators an adenine-enriched diet, which causes crystal precipitation in renal tubules, crystal-induced inflammasome activation, and renal fibrosis. We found that kidney fibrosis depended on an intrarenal inflammasome-dependent type 3 immune response driven by its signature transcription factor Rorc (retinoic acid receptor-related orphan receptor C gene), which was partially carried out by type 3 innate lymphoid cells (ILC3s). The role of ILCs in the kidney is less well known than in other organs, especially that of ILC3. In this article, we describe that depletion of ILCs or genetic deficiency for Rorc attenuated kidney inflammation and fibrosis. Among the inflammasome-derived cytokines, only IL-1ß expanded ILC3 and promoted fibrosis, whereas IL-18 caused differentiation of NKp46+ ILC3. Deficiency of the type 3 maintenance cytokine, IL-23, was more protective than IL-1ß inhibition, which may be explained by the downregulation of the IL-1R, but not of the IL-23R, by ILC3 early in the disease, allowing persistent sensing of IL-23. Mechanistically, ILC3s colocalized with renal MNPs in vivo as shown by multiepitope-ligand cartography. Cell culture experiments indicated that renal ILC3s caused renal MNPs to increase TGF-ß production that stimulated fibroblasts to produce collagen. We conclude that ILC3s link inflammasome activation with kidney inflammation and fibrosis and are regulated by IL-1ß and IL-23.


Asunto(s)
Fibrosis , Inmunidad Innata , Inflamasomas , Interleucina-23 , Linfocitos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Animales , Ratones , Inflamasomas/inmunología , Inflamasomas/metabolismo , Inmunidad Innata/inmunología , Linfocitos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Interleucina-23/inmunología , Interleucina-23/metabolismo , Riñón/inmunología , Riñón/patología , Ratones Noqueados , Ratones Endogámicos C57BL , Enfermedades Renales/inmunología , Enfermedades Renales/patología , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología
3.
Nat Immunol ; 13(5): 499-510, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22466668

RESUMEN

Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31(-) LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α(7). Together our data comprehensively describe the transcriptional characteristics of LNSC subsets.


Asunto(s)
Expresión Génica/inmunología , Inflamación/inmunología , Ganglios Linfáticos/inmunología , Células del Estroma/inmunología , Células del Estroma/metabolismo , Transcriptoma , Reacción de Fase Aguda/inmunología , Animales , Presentación de Antígeno/inmunología , Antígenos CD/inmunología , Antígenos CD/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Fibroblastos/inmunología , Fibroblastos/metabolismo , Homeostasis/inmunología , Inflamación/genética , Cadenas alfa de Integrinas/inmunología , Cadenas alfa de Integrinas/metabolismo , Interleucina-7/inmunología , Interleucina-7/metabolismo , Ganglios Linfáticos/citología , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Pericitos/inmunología , Pericitos/metabolismo , Autotolerancia/inmunología , Análisis de Matrices Tisulares/métodos
4.
Nat Immunol ; 12(11): 1096-104, 2011 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-21926986

RESUMEN

Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-γ, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses.


Asunto(s)
Selección Clonal Mediada por Antígenos , Endotelio Linfático/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células del Estroma/metabolismo , Linfocitos T/metabolismo , Animales , Procesos de Crecimiento Celular/genética , Movimiento Celular/genética , Células Cultivadas , Endotelio Linfático/inmunología , Endotelio Linfático/patología , Uniones Intercelulares/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Ganglios Linfáticos/patología , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/inmunología , Células del Estroma/inmunología , Células del Estroma/patología , Linfocitos T/inmunología , Linfocitos T/patología , Transgenes/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
5.
Cancer Cell Int ; 23(1): 3, 2023 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-36609378

RESUMEN

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.

6.
Immunol Invest ; 52(8): 966-984, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37846958

RESUMEN

BACKGROUND & AIMS: Vaccination with tumor-associated antigen-pulsed dendritic cells leads to specific T-cell response against hepatocellular carcinoma. However, clinical response has been shown to be limited. High regulatory T-cell count is associated with poor prognosis and seems to mediate immune tolerance in hepatocellular carcinoma. Forkhead box P3-peptide inhibitor P60 has been shown to specifically inhibit regulatory T-cell function in murine models. Aim of this study was to investigate whether P60 can improve the immune response induced by vaccination with adenovirus-transduced dendritic cells expressing alpha-fetoprotein in subcutaneous and orthotopic murine models for hepatocellular carcinoma. METHODS: Mice developing subcutaneous or orthotopic HCC received daily treatment with P60 starting at different tumor stages. Additionally, mice were vaccinated twice with dendritic cells expressing alpha-fetoprotein. RESULTS: In a preventive setting prior to tumor engraftment, vaccination with alpha-fetoprotein-expressing dendritic cells significantly decreased tumor growth in a subcutaneous model (p = .0256), but no further effects were achieved by addition of P60. However, P60 enhanced the antitumoral effect of a vaccination with alpha-fetoprotein-expressing dendritic cells in established subcutaneous and orthotopic hepatocellular carcinoma characterized by high Treg levels (p = .011). CONCLUSION: In this study, we showed that vaccination with alpha-fetoprotein-expressing dendritic cells in combination with a specific inhibition of regulatory T-cells by using P60 leads to synergistic tumor inhibition and prolonged survival. This emphasizes the importance of regulatory T-cells inhibition for obtaining an effective antitumoral immune response in hepatocellular carcinoma.


Asunto(s)
Vacunas contra el Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Linfocitos T Reguladores , Animales , Ratones , Adenoviridae , alfa-Fetoproteínas/genética , Carcinoma Hepatocelular/patología , Células Dendríticas , Inmunoterapia , Neoplasias Hepáticas/terapia , Linfocitos T Reguladores/efectos de los fármacos
7.
Nat Immunol ; 11(5): 427-34, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20305659

RESUMEN

A major pathway for B cell acquisition of lymph-borne particulate antigens relies on antigen capture by subcapsular sinus macrophages of the lymph node. Here we tested whether this mechanism is also important for humoral immunity to inactivated influenza virus. By multiple approaches, including multiphoton intravital imaging, we found that antigen capture by sinus-lining macrophages was important for limiting the systemic spread of virus but not for the generation of influenza-specific humoral immunity. Instead, we found that dendritic cells residing in the lymph node medulla use the lectin receptor SIGN-R1 to capture lymph-borne influenza virus and promote humoral immunity. Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Células Dendríticas/metabolismo , Endocitosis , Virus de la Influenza A/inmunología , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Anticuerpos Antivirales/sangre , Presentación de Antígeno , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/inmunología , Movimiento Celular , Células Cultivadas , Ácido Clodrónico/administración & dosificación , Dendrímeros/administración & dosificación , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Células Dendríticas/virología , Endocitosis/efectos de los fármacos , Endocitosis/genética , Inmunidad Humoral/efectos de los fármacos , Inmunidad Humoral/genética , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoterapia Activa , Virus de la Influenza A/patogenicidad , Vacunas contra la Influenza/administración & dosificación , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ganglios Linfáticos/patología , Ganglios Linfáticos/virología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Macrófagos/virología , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología
8.
Nat Immunol ; 11(4): 313-20, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20190758

RESUMEN

Cross-priming allows dendritic cells (DCs) to induce cytotoxic T cell (CTL) responses to extracellular antigens. DCs require cognate 'licensing' for cross-priming, classically by helper T cells. Here we demonstrate an alternative mechanism for cognate licensing by natural killer T (NKT) cells recognizing microbial or synthetic glycolipid antigens. Such licensing caused cross-priming CD8alpha(+) DCs to produce the chemokine CCL17, which attracted naive CTLs expressing the chemokine receptor CCR4. In contrast, DCs licensed by helper T cells recruited CTLs using CCR5 ligands. Thus, depending on the type of antigen they encounter, DCs can be licensed for cross-priming by NKT cells or helper T cells and use at least two independent chemokine pathways to attract naive CTLs. Because these chemokines acted synergistically, this can potentially be exploited to improve vaccinations.


Asunto(s)
Quimiocina CCL17/inmunología , Reactividad Cruzada/inmunología , Células Dendríticas/inmunología , Células T Asesinas Naturales/inmunología , Receptores CCR4/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Presentación de Antígeno/inmunología , Movimiento Celular/inmunología , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología
9.
Immunity ; 37(2): 276-89, 2012 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-22884313

RESUMEN

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.


Asunto(s)
Movimiento Celular/fisiología , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/metabolismo , Actinas/metabolismo , Inmunidad Adaptativa/fisiología , Animales , Células Presentadoras de Antígenos/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Células Dendríticas/inmunología , Embrión de Mamíferos , Células Endoteliales/metabolismo , Endotelio Linfático/citología , Endotelio Linfático/metabolismo , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Cadenas Ligeras de Miosina/metabolismo , Activación Plaquetaria , Embarazo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Transducción de Señal/fisiología , Piel/citología , Piel/metabolismo , Técnicas de Cultivo de Tejidos , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
10.
Semin Liver Dis ; 39(1): 70-77, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30654391

RESUMEN

Extracellular vesicles, comprising exosomes, microvesicles, and apoptotic bodies, represent an emerging field in disease diagnostics and prognosis. They can be isolated from peripheral blood of patients as well as from other body fluids and can therefore be considered a minimally invasive liquid biopsy screening tool. Especially their surface antigen composition can reveal information about disease backgrounds. For several liver diseases, including fatal hepatocellular and cholangiocellular carcinoma as well as other nonmalignant liver disorders such as nonalcoholic fatty liver disease, alcoholic hepatitis, or acute liver failure, it has been shown that extracellular vesicle (EV) surface profiling can be useful for disease diagnosis and prognosis. This review focuses on latest advances in these areas to improve liver disorder detection and management. Additionally, the authors will discuss possible therapeutic applications of EVs in liver diseases, which might be a potent treatment option in the future.


Asunto(s)
Micropartículas Derivadas de Células/fisiología , Exosomas/fisiología , Hepatopatías/diagnóstico , Animales , Biomarcadores/sangre , Humanos , Hepatopatías/terapia , Ratones
11.
Liver Int ; 39 Suppl 1: 63-78, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30907492

RESUMEN

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.


Asunto(s)
Neoplasias de los Conductos Biliares/inmunología , Colangiocarcinoma/inmunología , Células Endoteliales/inmunología , Fibroblastos/inmunología , Microambiente Tumoral/inmunología , Inmunidad Adaptativa , Animales , Neoplasias de los Conductos Biliares/fisiopatología , Colangiocarcinoma/fisiopatología , Modelos Animales de Enfermedad , Fibroblastos/patología , Humanos , Inmunidad Innata
13.
J Hepatol ; 66(3): 619-630, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27826058

RESUMEN

Liver progenitor cells (LPCs) are quiescent cells that are activated during liver injury and thought to give rise to hepatocytes and cholangiocytes in order to support liver regeneration and tissue restitution. While hepatocytes are capable of self-renewal, during most chronic injuries the proliferative capacity of hepatocytes is inhibited, thus LPCs provide main source for regeneration. Despite extensive lineage tracing studies, their role and involvement in these processes are often controversial. Additionally, increasing evidence suggests that the LPC compartment consists of heterogeneous cell populations that are actively involved in cellular interactions with myeloid and lymphoid cells during regeneration. On the other hand, LPC expansion has been associated with an increased fibrogenic response, raising concerns about the therapeutic use of these cells. This review aims to summarize the current understanding of the identity, the cellular interactions and the key pathways affecting the biology of LPCs. Understanding the regulatory circuits and the specific role of LPCs is especially important as it could provide novel therapeutic platforms for the treatment of liver inflammation, fibrosis and regeneration.


Asunto(s)
Hígado/citología , Hígado/lesiones , Células Madre/citología , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Hepatocitos/citología , Hepatocitos/fisiología , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Regeneración Hepática/fisiología , Nicho de Células Madre/fisiología , Células Madre/fisiología
14.
J Hepatol ; 66(6): 1241-1250, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28108233

RESUMEN

BACKGROUND & AIMS: Non-alcoholic fatty liver (NAFL) is the hepatic consequence of metabolic syndrome and can progress to non-alcoholic steatohepatitis (NASH). The identification of molecular and cellular factors that determine the progression of NASH and lead to irreversible hepatocellular damage are crucial. Dendritic cells (DCs) represent a heterogeneous cell population among which CD103+ DCs play a significant role in immunity and tolerance. We aimed to clarify the role of this DC subset in the pathomechanism of NASH. METHODS: Steatosis progression towards steatohepatitis was analysed using multicolor FACS analyses, cytokine and qPCR array in high sucrose diet (HSD) and methionine and choline deficient diet (MCD) fed wild-type and basic leucine zipper transcription factor, ATF-Like-3 (Batf3) deficient animals, which lack CD103+ DCs (classical type-1 DC, cDC1s). RESULTS: Metabolic challenge of Batf3-/- animals resulted in the progression of steatosis towards steatohepatitis, manifesting by an increased influx of inflammatory cells into the liver and elevated inflammatory cytokine production of myeloid cells upon innate stimuli. However, the lack of cDC1s did not affect cellular apoptosis and fibrosis progression but altered genes involved in lipid metabolism. The adoptive transfer of CD103+ cDC1s to Batf3 deficient animals reversed these observed changes and more importantly could attenuate cellular damage and inflammation in established murine steatohepatitis. CONCLUSION: Here, we have identified the murine CD103+ cDC1s as a protective DC subtype that influences the pro-anti-inflammatory balance and protects the liver from metabolic damage. As guardians of liver integrity, they play a key role in the inflammatory process during the development of steatohepatitis in mice. LAY SUMMARY: Non-alcoholic fatty liver (NAFL) is the hepatic consequence of metabolic syndrome and can lead to non-alcoholic steatohepatitis (NASH). The current study demonstrated that a specific murine dendritic cell subtype possesses a potent regulatory role to influence the inflammatory milieu of the liver in this process.


Asunto(s)
Antígenos CD/metabolismo , Células Dendríticas/inmunología , Cadenas alfa de Integrinas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Traslado Adoptivo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Citocinas/metabolismo , Células Dendríticas/clasificación , Células Dendríticas/metabolismo , Progresión de la Enfermedad , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Proteínas Represoras/deficiencia , Proteínas Represoras/genética
15.
J Hepatol ; 67(2): 282-292, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28267620

RESUMEN

BACKGROUND & AIMS: Large extracellular vesicles, specifically AnnexinV+ EpCAM+ CD147+ tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection and monitoring of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Specifically, the aim of this study was to differentiate liver taMPs from other cancer taMPs, such as CRC and NSCLC. METHODS: Fluorescence-activated cell scanning (FACS) was applied to detect various taMP populations in patients' sera that were associated with the presence of a tumour (AnnexinV+ EpCAM+ CD147+ taMPs) or could discriminate between cirrhosis (due to HCV or HBV) and liver cancers (AnnexinV+ EpCAM+ ASGPR1+ taMPs). In total 172 patients with liver cancer (HCC or CCA), 54 with cirrhosis and no liver neoplasia, and 202 control subjects were enrolled. RESULTS: The results indicate that AnnexinV+ EpCAM+ CD147+ taMPs were elevated in HCC and CCA. Furthermore, AnnexinV+ EpCAM+ ASGPR1+ CD133+ taMPs allowed the distinction of liver malignancies (HCC or CCA) and cirrhosis from tumour-free individuals and, more importantly, from patients carrying other non-liver cancers. In addition, AnnexinV+ EpCAM+ ASGPR1+ taMPs were increased in liver cancer-bearing patients compared to patients with cirrhosis that lacked any detectable liver malignancy. The smallest sizes of successfully detected cancers were ranging between 11-15mm. AnnexinV+ EpCAM+ ASGPR1+ taMPs decreased at 7days after curative R0 tumour resection suggesting close correlations with tumour presence. ROC values, sensitivity/specificity scores and positive/negative predictive values (>78%) indicated a potent diagnostic accuracy of AnnexinV+ EpCAM+ ASGPR1+ taMPs. CONCLUSION: These data provide strong evidence that AnnexinV+ EpCAM+ ASGPR1+ taMPs are a novel biomarker of HCC and CCA liquid biopsy that permit a non-invasive assessment of the presence and possible extent of these cancers in patients with advanced liver diseases. LAY SUMMARY: Microparticles (MPs) are small vesicles that bleb from the membrane of every cell, including cancer cells, and are released to circulate in the bloodstream. Since their surface composition is similar to the surface of their underlying parental cell, MPs from the bloodstream can be isolated and by screening their surface components, the presence of their parental cells can be identified. This way, it was possible to detect and discriminate between patients bearing liver cancer and chronic liver cirrhosis.


Asunto(s)
Neoplasias de los Conductos Biliares/sangre , Carcinoma Hepatocelular/sangre , Micropartículas Derivadas de Células/patología , Colangiocarcinoma/sangre , Neoplasias Hepáticas/sangre , Adulto , Anciano , Anexina A5/sangre , Receptor de Asialoglicoproteína/sangre , Basigina/sangre , Neoplasias de los Conductos Biliares/diagnóstico , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/diagnóstico , Línea Celular Tumoral , Colangiocarcinoma/diagnóstico , Diagnóstico Diferencial , Molécula de Adhesión Celular Epitelial/sangre , Femenino , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Carga Tumoral , Adulto Joven
16.
Am J Physiol Gastrointest Liver Physiol ; 310(1): G1-12, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26564718

RESUMEN

Podoplanin/gp38(+) stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38(+) cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38(+) cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38(+) cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38(+) cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45(-)CD31(-)Asgpr1(-) liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38(hi)CD133(-), gp38(low)CD133(-), and gp38(-)CD133(-)). Moreover, among the CD133(+) cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38(-)CD133(+) and CD133(+)gp38(+)). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38(+)CD133(+) cells exhibited liver progenitor cell characteristics similar to the gp38(-)CD133(+) population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Experimental/metabolismo , Hígado/metabolismo , Glicoproteínas de Membrana/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Células Madre/metabolismo , Células del Estroma/metabolismo , Antígeno AC133 , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Separación Celular/métodos , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citometría de Flujo , Regulación de la Expresión Génica , Glicoproteínas/metabolismo , Mediadores de Inflamación/metabolismo , Hígado/patología , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Péptidos/metabolismo , Fenotipo , Células Madre/patología , Células del Estroma/patología , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
17.
Eur J Immunol ; 44(2): 500-10, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24136200

RESUMEN

The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α⁻CD11b⁺ LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α⁻ and CD8α⁺ splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b⁺ DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b⁺CCL17⁺ DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.


Asunto(s)
Diferenciación Celular/inmunología , Microambiente Celular/inmunología , Células Dendríticas/metabolismo , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Receptores de Interferón/metabolismo , Bazo/metabolismo , Animales , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , Quimiocina CCL17/inmunología , Quimiocina CCL17/metabolismo , Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interferón gamma/inmunología , Interleucina-4/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Interferón/deficiencia , Receptores de Interferón/inmunología , Bazo/inmunología , Receptor de Interferón gamma
18.
Liver Int ; 34(3): 447-61, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23998316

RESUMEN

BACKGROUND: Interleukin 12 (IL-12), one of the most potent Th1-cytokines, has been used to improve dendritic cells (DC)-based immunotherapy of cancer. However, it failed to achieve clinical response in patients with hepatocellular carcinoma (HCC). In this study, improved conditions of immunotherapy with DC engineered to express IL-12 were studied in murine subcutaneous HCC. METHODS: Tumour-lysate pulsed DC were transduced with IL-12-encoding adenoviruses or cultivated with recombinant (r)IL-12. DC were injected intratumourally, subcutaneously or intravenously at different stages of tumour-development. RESULTS: Dendritic cell overexpressing IL-12 by adenoviruses showed enhanced expression of costimulatory molecules and stronger priming of HCC-specific effector cells than DC cultured with rIL-12. Intratumoural but not systemic injections of IL-12-DC induced the strongest antitumoural effects reaching complete regressions in 75% of early-staged tumours and in 33% of advanced tumours. Importantly, antitumoural effects could be further enhanced through combination with sorafenib. Analysing the tumour-environment, IL-12-DC increased the levels of Th1-cytokines/chemokines and of CD4(+) -, CD8(+) -T- and NK-cells. Induced immunity was tumour-specific and sustained since all tumour-free animals were protected towards hepatic tumour-cell rechallenge. However, IL-12-DC also enhanced immunosuppressive cytokines, regulatory T cells and even myeloid-derived suppressor cells within the tumours. CONCLUSIONS: Induced IL-12-overexpression by adenoviral vectors can effectively immunostimulate DC. Intratumoural but not systemic injection of activated IL-12-DC was crucial for effective tumour regression. The mechanism of this approach seems to be the induction of a sufficient Th1 tumour-environment allowing the recruitment of effector cells rather than the inhibition of tumour immunosuppression. Thus, improved immunotherapy with IL-12-DC represents a promising approach towards HCC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/terapia , Células Dendríticas/inmunología , Interleucina-12/genética , Neoplasias Hepáticas/terapia , Adenoviridae/genética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Citotoxicidad Inmunológica , Humanos , Inmunoterapia , Ratones , Ratones Endogámicos C3H , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Sorafenib
19.
Front Immunol ; 15: 1379225, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38650949

RESUMEN

Dendritic cells (DCs) are major antigen-presenting cells that connect innate and adaptive immunity. Hepatic DCs are less activated and contribute to maintain the tolerogenic environment of the liver under steady state. Several studies indicated DCs in metabolic dysfunction-associated steatohepatitis (MASH), representing a substantial burden on healthcare systems due to its association with liver-related morbidity and mortality. Studies highlighted the potential disease-promoting role of liver DCs in the development of MASH while other experimental systems suggested their protective role. This review discusses this controversy and the current understanding of how DCs affect the pathogenesis of MASH.


Asunto(s)
Células Dendríticas , Células Dendríticas/inmunología , Humanos , Animales , Hígado/inmunología , Hígado Graso/inmunología
20.
J Diabetes Complications ; 38(8): 108796, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38991491

RESUMEN

AIMS: To elucidate the clinical and pathological characteristics of gestational diabetes mellitus (GDM) with high and low insulin resistance. METHODS: In total, 1393 GDM and 1001 non-GDM singleton deliveries were included in this study. Insulin resistance subtypes were classified according to the HOMA2-IR value. Clinical data were analyzed using SPSS 26.0. Placenta samples were collected for pathological analysis. RESULTS: Maternal age and fasting glucose were identified as independent risk factors for GDM with high insulin resistance (p < 0.01), while fasting glucose was the sole risk factor for GDM with low insulin resistance (p < 0.001). Fetal distress was associated with both of GDM subtypes (both p < 0.01), while anemia, fetal growth restriction, large for gestational age and intrahepatic cholestasis in pregnancy were related to specific GDM insulin resistance subtype. In addition, GDM with high insulin resistance showed an increase of syncytial knots with down-regulation of PI3K/AKT signaling, while GDM with low insulin resistance showed normal syncytial knot counts and up-regulation of PI3K/AKT signaling. CONCLUSIONS: Our findings provide novel perspectives to the clinical and pathological comprehensions of GDM with high and low insulin resistance, which might facilitate the mechanism study of GDM and its precision pregnancy management.


Asunto(s)
Diabetes Gestacional , Resistencia a la Insulina , Placenta , Humanos , Embarazo , Femenino , Resistencia a la Insulina/fisiología , Adulto , Placenta/patología , Placenta/metabolismo , Glucemia/análisis , Glucemia/metabolismo , Factores de Riesgo , Edad Materna , Transducción de Señal
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