NLRP12 controls arthritis severity by acting as a checkpoint inhibitor of Th17 cell differentiation

Autor(es)

Prado, Douglas Silva ^{[1, 2]} ; Veras, Flavio P. ^{[1, 2]} ; Ferreira, Raphael Gomes ^{[1, 2]} ; Damasceno, Luis Eduardo Alves ^{[1, 2]} ; Melo, Paulo Henrique ^{[1, 2]} ; Zamboni, Dario Simoes ^{[3, 2]} ; Cunha, Thiago Mattar ^{[1, 2]} ; Cunha, Fernando Queiroz ^{[1, 2]} ; Alves-Filho, Jose Carlos ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, CRID, Ctr Res Inflammatory Dis, Ribeirao Preto - Brazil

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

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 34, n. 8 JUL 2020.
• Citações Web of Science: 0

Resumo

Nucleotide oligomerization domain (NOD)-like receptor-12 (NLRP12) has emerged as a negative regulator of inflammation. It is well described that the Th17 cell population increases in patients with early Rheumatoid Arthritis (RA), which correlates with the disease activity. Here, we investigated the role of NLRP12 in the differentiation of Th17 cells and the development of experimental arthritis, using the antigen-induced arthritis (AIA) murine model. We found thatNlrp12(-/)(-)mice develop severe arthritis characterized by an exacerbated Th17-mediated inflammatory response with increases in the articular hyperalgesia, knee joint swelling, and neutrophil infiltration. Adoptive transfer ofNlrp12(-/)(-)cells into WT mice recapitulated the hyperinflammatory response seen inNlrp12(-/)(-)mice and the treatment with anti-IL-17A neutralizing antibody abrogated arthritis development inNlrp12(-/)(-)mice, suggesting that NLRP12 works as an inhibitor of Th17 cell differentiation. Indeed, Th17 cell differentiation markedly increases inNlrp12(-/-)T cells cultured under the Th17-skewing condition. Mechanistically, we found that NLRP12 negatively regulates IL-6-induced phosphorylation of STAT3 in T cells. Finally, pharmacological inhibition of STAT3 reduced Th17 cell differentiation and abrogated hyperinflammatory arthritis observed inNlrp12(-/)(-)mice. Thus, we described a novel role for NLRP12 as a checkpoint inhibitor of Th17 cell differentiation, which controls the severity of experimental arthritis. (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: 16/05377-3 - Importância da via de sinalização dependente de ERK5 na diferenciação de linfócitos Th17 e Treg e no desenvolvimento da encefalomielite autoimune experimental
• Beneficiário: Douglas da Silva Prado
• Modalidade de apoio: Bolsas no Brasil - Doutorado