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1.
Nat Immunol ; 22(2): 166-178, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33432227

RESUMEN

Type 2 innate lymphoid cells (ILC2) contribute to immune homeostasis, protective immunity and tissue repair. Here we demonstrate that functional ILC2 cells can arise in the embryonic thymus from shared T cell precursors, preceding the emergence of CD4+CD8+ (double-positive) T cells. Thymic ILC2 cells migrated to mucosal tissues, with colonization of the intestinal lamina propria. Expression of the transcription factor RORα repressed T cell development while promoting ILC2 development in the thymus. From RNA-seq, assay for transposase-accessible chromatin sequencing (ATAC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) data, we propose a revised transcriptional circuit to explain the co-development of T cells and ILC2 cells from common progenitors in the thymus. When Notch signaling is present, BCL11B dampens Nfil3 and Id2 expression, permitting E protein-directed T cell commitment. However, concomitant expression of RORα overrides the repression of Nfil3 and Id2 repression, allowing ID2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORα expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Linaje de la Célula , Inmunidad Innata , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Timocitos/metabolismo , Timo/metabolismo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Femenino , Regulación del Desarrollo de la Expresión Génica , Proteína 2 Inhibidora de la Diferenciación/genética , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Técnicas de Cultivo de Órganos , Fenotipo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Timocitos/inmunología , Timo/embriología , Timo/inmunología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
2.
Acta Neuropathol Commun ; 9(1): 189, 2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34819144

RESUMEN

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.


Asunto(s)
Enfermedades Neurodegenerativas/patología , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacología , Anciano , Animales , Animales Modificados Genéticamente , Miembro Posterior , Humanos , Inmunohistoquímica , Masculino , Ratones Mutantes Neurológicos , Microglía/patología , Neuronas Motoras/patología , Trastornos del Movimiento/patología , Atrofia de Múltiples Sistemas/patología , Mutación , Enfermedades Neurodegenerativas/inducido químicamente , Neuronas/metabolismo , Parálisis/inducido químicamente , Parálisis/patología , alfa-Sinucleína/administración & dosificación
3.
Sci Rep ; 11(1): 21584, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34732748

RESUMEN

The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-ß-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.


Asunto(s)
Senescencia Celular , Fibrosis/metabolismo , Proteína Fosfatasa 1/genética , Respuesta de Proteína Desplegada , Anciano , Animales , Bleomicina , Diferenciación Celular , Proliferación Celular , Estrés del Retículo Endoplásmico , Femenino , Fibroblastos/metabolismo , Genotipo , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Indoles/farmacología , Pulmón/metabolismo , Masculino , Mesodermo/citología , Ratones , Persona de Mediana Edad , Morfolinas/farmacología , Proteína Fosfatasa 1/fisiología , Análisis de Secuencia de ARN , Factor de Crecimiento Transformador beta/metabolismo
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