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1.
Ann Rheum Dis ; 76(3): 620-625, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28039186

RESUMEN

OBJECTIVE: To determine the microRNA (miR) signature in ankylosing spondylitis (AS) T helper (Th)17 cells. METHODS: Interleukin (IL)-17A-producing CD4+ T cells from patients with AS and healthy controls were FACS-sorted for miR sequencing and qPCR validation. miR-10b function was determined by miR mimic expression followed by cytokine measurement, transcriptome analysis, qPCR and luciferase assays. RESULTS: AS Th17 cells exhibited a miR signature characterised by upregulation of miR-155-5p, miR-210-3p and miR-10b. miR-10b has not been described previously in Th17 cells and was selected for further characterisation. miR-10b is transiently induced in in vitro differentiated Th17 cells. Transcriptome, qPCR and luciferase assays suggest that MAP3K7 is targeted by miR-10b. Both miR-10b overexpression and MAP3K7 silencing inhibited production of IL-17A by both total CD4 and differentiating Th17 cells. CONCLUSIONS: AS Th17 cells have a specific miR signature and upregulate miR-10b in vitro. Our data suggest that miR-10b is upregulated by proinflammatory cytokines and may act as a feedback loop to suppress IL-17A by targeting MAP3K7. miR-10b is a potential therapeutic candidate to suppress pathogenic Th17 cell function in patients with AS.


Asunto(s)
Interleucina-17/biosíntesis , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Células Th17/metabolismo , Regulación hacia Arriba , Adulto , Anciano , Linfocitos T CD4-Positivos/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Femenino , Silenciador del Gen , Humanos , Interleucina-6/farmacología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Persona de Mediana Edad , Espondilitis Anquilosante , Transcriptoma/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Adulto Joven
2.
Nat Commun ; 8(1): 1510, 2017 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-29142230

RESUMEN

Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Espondiloartritis/genética , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Animales , Femenino , Estudio de Asociación del Genoma Completo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Espondiloartritis/metabolismo , Adulto Joven
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