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1.
J Immunol ; 205(11): 3001-3010, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33127821

RESUMEN

The voltage-gated proton channel Hv1 regulates proton fluxes across membranes, thereby influencing pH-dependent processes. Plasmacytoid dendritic cells (pDCs) require a particularly tight regulation of endosomal pH to ensure strong type I IFN secretion exclusively during infection, avoiding autoimmunity. However, whether Hv1 is important for pH control in pDCs is presently unknown. In this study, we show that mouse pDCs require Hv1 to achieve potent type I IFN responses after the recognition of foreign DNA by endosomal TLR9. Genetic disruption of Hvcn1, which encodes Hv1, impaired mouse pDC activation by CpG oligonucleotides in vitro and in vivo, reducing IFN-α secretion and the induction of IFN-stimulated genes. Mechanistically, Hvcn1 deficiency delayed endosomal acidification and enhanced intracellular reactive oxygen species production, consequently limiting protease activity and TLR9 signaling. Our study reveals a critical role of Hv1 during innate immune responses and places this channel as a key modulator of type I IFN production, the hallmark function of pDCs, commending Hv1 as an attractive target for modulating type I IFN-driven autoimmunity.


Asunto(s)
Células Dendríticas/metabolismo , Canales Iónicos/metabolismo , Receptor Toll-Like 9/metabolismo , Animales , Inmunidad Innata/fisiología , Interferón-alfa/metabolismo , Ratones , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología
2.
Sci Transl Med ; 14(630): eabm3682, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-35108063

RESUMEN

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.


Asunto(s)
Enfermedad de Huntington , Enfermedades Neurodegenerativas , Animales , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Ligandos , Enfermedades Neurodegenerativas/patología
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