TGF-beta signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis

Autor(es):Mostrar menos -

Peres, Raphael S. ^{[1, 2]} ; Donate, Paula B. ^[1] ; Talbot, Jhimmy ^[1] ; Cecilio, Nerry T. ^[1] ; Lobo, Patricia R. ^[3] ; Machado, Caio C. ^[3] ; Lima, Kalil W. A. ^[1] ; Oliveira, Rene D. ^[3] ; Carregaro, Vanessa ^[4] ; Nakaya, I, Helder ; Cunha, Thiago M. ^[1] ; Alves-Filho, Jose Carlos ^[1] ; Liew, Foo Y. ^{[5, 6]} ; Louzada-Junior, Paulo ^[3] ; Cunha, Fernando Q. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[2] Univ Oxford, Kennedy Inst Rheumatol, Oxford - England

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil

^[5] Soochow Univ, Sch Biol & Basic Med Sci, Suzhou 215006 - Peoples R China

^[6] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark - Scotland

• Tipo de documento: Artigo Científico
• Fonte: Journal of Autoimmunity; v. 90, p. 49-58, JUN 2018.
• Citações Web of Science: 7

Resumo

Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-beta signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-beta increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPDI gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREBI and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance. (C) 2018 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 12/10438-0 - Associação da expressão de CD39 em células Tregs com a eficácia terapêutica do metotrexato no tratamento da artrite reumatoide
• Beneficiário: Raphael Sanches Peres
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/54014-7 - EMU: aquisição dos equipamentos IVIS Spectrum e microscópio de excitação por dois fótons para imagem in vivo
• Beneficiário: Enilza Maria Espreafico
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários