Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling

Abstract

IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.

Monocytes and CD4 + T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with multiple sclerosis

“…NR4A2 was also seen to direct the development of both Treg (Sekiya et al, 2013) and Th17 (Raveney et al, 2013) cells, resulting respectively in the protection and exacerbation of autoimmune diseases.…”

“…On one hand, it has been demonstrated that NR4A2 is involved in controlling the transcription of NF-κB target genes (Saijo et al, 2009), and in the development of Treg cells (Sekiya et al, 2011 andSekiya et al, 2013); its low expression has been correlated with MS , Achiron et al, 2010. On the other hand, it has been shown to have a role in the differentiation of Th17 cells (Raveney et al, 2013) and to be overexpressed in a population of Japanese MS patients (Satoh et al, 2005).…”

Nuclear receptor 4A (NR4A) family – orphans no more

“…NR4A2 also influences maturation and differentiation of Th17 T-cells and may thereby have a role in both autoimmunity and in resolution of infections [160]. NR4A2, but not NR4A1 or NR4A3, is upregulated in rheumatoid arthritis, where its expression is induced by PGE2, IL-1β, and TNF-α [161], suggesting that this factor may have broad effects in limiting inflammatory responses through its function as a transrepressor of the NFκB pathway.…”

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

“…87 The genetic ablation of Nr4a2 in CD41 T cells resulted in a failure to induce Th17 differentiation in vitro. Similarly, siRNA-mediated gene silencing of Nr4a2 in T cells ameliorated pathogenesis in murine EAE.…”