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

Abstract

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.

• Authors: Douglas Silva Prado, Flavio P Veras, Raphael Gomes Ferreira, Luis Eduardo Alves Damasceno, Paulo Henrique Melo, Dario Simões Zamboni, Thiago Mattar Cunha, Fernando Queiroz Cunha, José Carlos Alves-Filho
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 8 Pg. 10907-10919 (08 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32632939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• Interleukin-17
• Intracellular Signaling Peptides and Proteins
• NLRP12 protein, mouse
• STAT3 Transcription Factor

Topics

• Animals
• Arthritis, Experimental (metabolism, pathology)
• Arthritis, Rheumatoid (metabolism, pathology)
• Cell Differentiation (physiology)
• Inflammation (metabolism, pathology)
• Interleukin-17 (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Joints (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration (physiology)
• STAT3 Transcription Factor (metabolism)
• Th17 Cells (metabolism, pathology)