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NLRP12 controls arthritis severity by acting as a checkpoint inhibitor of Th17 cell differentiation
Author(s) -
Prado Douglas Silva,
Veras Flavio P.,
Ferreira Raphael Gomes,
Damasceno Luis Eduardo Alves,
Melo Paulo Henrique,
Zamboni Dario Simões,
Cunha Thiago Mattar,
Cunha Fernando Queiroz,
AlvesFilho José Carlos
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000795r
Subject(s) - arthritis , inflammation , immunology , interleukin 17 , adoptive cell transfer , medicine , rheumatoid arthritis , cellular differentiation , cancer research , t cell , chemistry , immune system , biochemistry , gene
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 that Nlrp12 −/ − 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 of Nlrp12 −/ − cells into WT mice recapitulated the hyperinflammatory response seen in Nlrp12 −/ − mice and the treatment with anti‐IL‐17A neutralizing antibody abrogated arthritis development in Nlrp12 −/ − mice, suggesting that NLRP12 works as an inhibitor of Th17 cell differentiation. Indeed, Th17 cell differentiation markedly increases in Nlrp12 −/− 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 in Nlrp12 −/ − mice. Thus, we described a novel role for NLRP12 as a checkpoint inhibitor of Th17 cell differentiation, which controls the severity of experimental arthritis.