3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Takaichi Okano,Akio Morinobu,Yo Ueda,Keisuke Nishimura,Soshi Takahashi,Jun Saegusa,Sho Sendo

doi:10.1038/srep42412

Abstract

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

Highlights

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions
A recent report suggests that Dendritic cells (DCs) activation requires an increase in glycolysis[11], while fatty acid oxidation (FAO) is important in tolerogenic DCs12
We show for the first time that BrPA ameliorates SKG arthritis, facilitates the differentiation of Treg cells, and suppresses Th17 cells

Summary

Results

Lymphocytes in the synovium of RA patients express HK2. HK2 expression in the synovitis tissue of RA patients was examined by immunohistochemistry. BrPA treatment significantly decreased the severity of the arthritis in the SKG mice compared to the NS-treated control group (Fig. 2A). BrPA significantly reduced the severity of synovial hyperplasia and pannus formation, and the extent of bone destruction (Fig. 2B, C) These results suggest that BrPA ameliorates the arthritis in SKG mice. ELISAs revealed decreased levels of these cytokines in the supernatant of 80 μM BrPA-treated cells (Fig. 5C, D) These result strongly suggested that BrPA ameliorates inflammation in SKG arthritis by facilitating the differentiation of Treg cells and by suppressing the activation of DCs. BrPA halts the progression of ongoing arthritis. We confirmed that the lymphocytes infiltrating the synovium of NS-treated mice expressed HK2 (Fig. 6C)

Discussion

Conclusion

Methods