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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 9
[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
Total Affiliations: 3
Document type: Journal article
Source: FASEB JOURNAL; v. 34, n. 8 JUL 2020.
Web of Science Citations: 0

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)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 16/05377-3 - Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis
Grantee:Douglas da Silva Prado
Support Opportunities: Scholarships in Brazil - Doctorate