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1.
Int J Mol Sci ; 24(5)2023 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-36902241

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice.


Asunto(s)
Células Estrelladas Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Molécula 1 de Adhesión Celular Vascular , Animales , Ratones , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Inflamación/metabolismo , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Modelos Animales de Enfermedad
2.
Nat Immunol ; 18(6): 654-664, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28414311

RESUMEN

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.


Asunto(s)
Adipocitos Beige , Adipogénesis/inmunología , Tejido Adiposo Blanco/inmunología , Diferenciación Celular/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Adipocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Adhesión Celular/inmunología , Dieta Alta en Grasa , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Retroalimentación , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Integrina alfa4/genética , Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Monocitos/inmunología , Obesidad/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Grasa Subcutánea , Linfocitos T/inmunología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adulto Joven
3.
Immunity ; 37(5): 867-79, 2012 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-23142781

RESUMEN

The genome of vertebrates contains endogenous retroviruses (ERVs) that are largely nonfunctional relicts of ancestral germline infection by exogenous retroviruses. However, in some mouse strains ERVs are actively involved in disease. Here we report that nucleic acid-recognizing Toll-like receptors 3, 7, and 9 (TLR 3, TLR7, and TLR9) are essential for the control of ERVs. Loss of TLR7 function caused spontaneous retroviral viremia that coincided with the absence of ERV-specific antibodies. Importantly, additional TLR3 and TLR9 deficiency led to acute T cell lymphoblastic leukemia, underscoring a prominent role for TLR3 and TLR9 in surveillance of ERV-induced tumors. Experimental ERV infection induced a TLR3-, TLR7-, and TLR9-dependent group of "acute-phase" genes previously described in HIV and SIV infections. Our study suggests that in addition to their role in innate immunity against exogenous pathogens, nucleic acid-recognizing TLRs contribute to the immune control of activated ERVs and ERV-induced tumors.


Asunto(s)
Retrovirus Endógenos/genética , Ácidos Nucleicos/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Viremia/genética , Animales , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Línea Celular , Retrovirus Endógenos/inmunología , Retrovirus Endógenos/metabolismo , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ácidos Nucleicos/inmunología , Ácidos Nucleicos/metabolismo , Oncogenes/genética , Oncogenes/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Toll-Like/inmunología , Viremia/inmunología , Viremia/metabolismo
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