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1.
J Neuroimmunol ; 359: 577675, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34403862

RESUMEN

Myelin-specific CD4 T effector cells (Teffs), Th1 and Th17 cells, are encephalitogenic in experimental autoimmune encephalomyelitis (EAE), a well-defined murine model of multiple sclerosis (MS) and implicated in MS pathogenesis. Forkhead box O 1 (FoxO1) is a conserved effector molecule in PI3K/Akt signaling and critical in the differentiation of CD4 T cells into T helper subsets. However, it is unclear whether FoxO1 may be a target for redirecting CD4 T cell differentiation and benefit CNS autoimmunity. Using a selective FoxO1 inhibitor AS1842856, we show that inhibition of FoxO1 suppressed the differentiation and expansion of Th1 cells. The transdifferentiation of Th17 cells into encephalitogenic Th1-like cells was suppressed by FoxO1 inhibition upon reactivation of myelin-specific CD4 T cells from EAE mice. The transcriptional balance skewed from the Th1 transcription factor T-bet toward the Treg transcription factor Foxp3. Myelin-specific CD4 T cells treated with the FoxO1 inhibitor were less encephalitogenic in adoptive transfer EAE studies. Inhibition of FoxO1 in T cells from MS patients significantly suppressed the expansion of Th1 cells. Furthermore, FoxO1 inhibition with AS1842856 promoted the development of functional iTreg cells. The immune checkpoint programmed cell death protein-1 (PD-1)-induced Foxp3 expression in CD4 T cells was impaired by FoxO1 inhibition. These data illustrate an important role of FoxO1 signaling in CNS autoimmunity via regulating autoreactive Teff and Treg balance.


Asunto(s)
Autoinmunidad/fisiología , Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Proteína Forkhead Box O1/inmunología , Esclerosis Múltiple/inmunología , Adulto , Animales , Autoinmunidad/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Proteína Forkhead Box O1/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Quinolonas/farmacología
2.
Glia ; 68(7): 1445-1465, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32034934

RESUMEN

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas. Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.


Asunto(s)
Inflamación/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Regeneración Nerviosa/fisiología , Regeneración/fisiología , Animales , Animales Modificados Genéticamente , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Neuroglía/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastones/fisiología , Células Madre/fisiología , Pez Cebra
3.
J Comp Neurol ; 477(1): 108-17, 2004 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-15281083

RESUMEN

Persistent rod genesis in the retinas of teleost fish was first described over 2 decades ago, but little is known regarding the underlying genetic and molecular mechanisms that govern this phenomenon. Because of its function in the developing mammalian retina and persistently mitotic adult tissues, we sought to characterize the cellular expression of the basic helix-loop-helix (bHLH) transcription factor neuroD in the persistently neurogenic retina of adult teleosts. We show here that, in the adult retina of the goldfish, neuroD is expressed by putative amacrine cells, nascent cones, and the mitotically active cells of the rod lineage. neuroD is the first gene shown to be expressed by rod precursors, the immediate antecedents of rod photoreceptors. In contrast to the vertebrate classes described previously, neuroD is not expressed in multipotent progenitors in the teleost retina. Combining neuroD in situ hybridizations with cell-cycle-specific markers suggests that, in rod precursors, neuroD expression is cell cycle specific.


Asunto(s)
Expresión Génica/fisiología , Proteínas del Tejido Nervioso/metabolismo , Retina/citología , Células Fotorreceptoras Retinianas Bastones/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Bromodesoxiuridina/metabolismo , Proteína Quinasa CDC2/metabolismo , Recuento de Células/métodos , Ciclo Celular/fisiología , Expresión Génica/efectos de los fármacos , Carpa Dorada , Hormona del Crecimiento/administración & dosificación , Agonistas de los Receptores Histamínicos/metabolismo , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Células Fotorreceptoras Retinianas Bastones/efectos de los fármacos , Factores de Tiempo
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