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1.
Immunity ; 44(4): 901-12, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-27096319

RESUMEN

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.


Asunto(s)
Encéfalo/citología , Quimiocina CXCL10/inmunología , Trastornos del Conocimiento/genética , Células Endoteliales/inmunología , Células Epiteliales/inmunología , Conducta de Enfermedad/fisiología , Receptor de Interferón alfa y beta/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Encéfalo/inmunología , Comunicación Celular/inmunología , Células Cultivadas , Trastornos del Conocimiento/psicología , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/metabolismo , Endotelio/citología , Endotelio/inmunología , Epitelio/inmunología , Interferón Tipo I/uso terapéutico , Helicasa Inducida por Interferón IFIH1 , Masculino , Ratones , ARN Bicatenario/genética , Receptor de Interferón alfa y beta/inmunología , Receptores CXCR3/inmunología , Transducción de Señal/inmunología , Virosis/inmunología
2.
EMBO J ; 34(12): 1612-29, 2015 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-25896511

RESUMEN

Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.


Asunto(s)
Encéfalo/metabolismo , Endopeptidasas/deficiencia , Interferones/metabolismo , Microglía/metabolismo , Modelos Neurológicos , Transducción de Señal/fisiología , Animales , Western Blotting , Clonación Molecular , Cartilla de ADN/genética , Endopeptidasas/genética , Endopeptidasas/metabolismo , Técnicas Histológicas , Ratones , Ratones Noqueados , Análisis por Micromatrices , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Estadísticas no Paramétricas , Ubiquitina Tiolesterasa
3.
Proc Natl Acad Sci U S A ; 110(4): 1494-9, 2013 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-23297198

RESUMEN

Soluble cytosolic carbonic anhydrases (CAs) are well known to participate in pH regulation of the cytoplasm of mammalian cells. Membrane-bound CA isoforms--such as isoforms IV, IX, XII, XIV, and XV--also catalyze the reversible conversion of carbon dioxide to protons and bicarbonate, but at the extracellular face of the cell membrane. When human CA isoform IV was heterologously expressed in Xenopus oocytes, we observed, by measuring H(+) at the outer face of the cell membrane and in the cytosol with ion-selective microelectrodes, not only extracellular catalytic CA activity but also robust intracellular activity. CA IV expression in oocytes was confirmed by immunocytochemistry, and CA IV activity measured by mass spectrometry. Extra- and intracellular catalytic activity of CA IV could be pharmacologically dissected using benzolamide, the CA inhibitor, which is relatively slowly membrane-permeable. In acute cerebellar slices of mutant mice lacking CA IV, cytosolic H(+) shifts of granule cells following CO(2) removal/addition were significantly slower than in wild-type mice. Our results suggest that membrane-associated CA IV contributes robust catalytic activity intracellularly, and that this activity participates in regulating H(+) dynamics in the cytosol, both in injected oocytes and in mouse neurons.


Asunto(s)
Anhidrasa Carbónica IV/metabolismo , Animales , Benzolamida/farmacología , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/genética , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica IV/antagonistas & inhibidores , Anhidrasa Carbónica IV/deficiencia , Anhidrasa Carbónica IV/genética , Inhibidores de Anhidrasa Carbónica/farmacología , Cerebelo/citología , Cerebelo/enzimología , Citosol/enzimología , Líquido Extracelular/enzimología , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Líquido Intracelular/enzimología , Ratones , Ratones Noqueados , Neuronas/enzimología , Oocitos/enzimología , ARN Complementario/genética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Xenopus laevis
4.
Acta Neuropathol Commun ; 4(1): 102, 2016 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-27639555

RESUMEN

Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1 (-/-) mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1 (+/-) or cx3cr1 (+/+) controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx3cr1 (-/-) mice. Remarkably, adult neurogenesis was not affected by the lack of the CX3CR1-ligand, fractalkine (CX3CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx3cr1 (-/-) mice in a hippocampus-dependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx3cr1 (-/-) mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX3CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX3CL1.


Asunto(s)
Células Madre Adultas/metabolismo , Microglía/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Receptores de Interleucina-8A/metabolismo , Células Madre Adultas/efectos de los fármacos , Animales , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Proteínas de Dominio Doblecortina , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/citología , Microglía/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/metabolismo , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuropéptidos/metabolismo , Receptores de Interleucina-8A/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/metabolismo , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiología , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/metabolismo
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