Dual Effect of 3-Bromopyruvate on Both Th17 and Treg Cell Differentiation and Dendritic Cell Activation Ameliorates Autoimmune Arthritis in Mice

Takaichi Okano¹, Jun Saegusa², Keisuke Nishimura³, Yo Ueda⁴, Sho Sendo², Soshi Takahashi⁵, Kengo Akashi³, Akira Onishi⁶ and Akio Morinobu², ¹Rheumatology and Clinical immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ²Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ³Department of Rheumatology, Kobe University Hospital, Kobe, Japan, ⁴Kobe University Graduate School of Medicine, Kobe, Japan, ⁵Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ⁶Department for Rheumatology, Kobe University Hospital, Kobe, Japan

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Arthritis, dendritic cells and metabolism, T cells, T-Regulatory Cells

Session Information

Date: Sunday, November 13, 2016

Title: Rheumatoid Arthritis – Animal Models - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Recent studies have shown that cellular metabolism plays an important role in regulating immune cell function. In the process of cell differentiation, both interleukin-17-producing helper T (Th17) cells and dendritic cells (DCs) show increase of glycolytic activity by upregulating glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis by 2-deoxyglucose has recently been demonstrated to inhibits Th17 cell differentiation while promotes regulatory T (Treg) cell generation, and then ameliorates experimental autoimmune encephalitis model. In addition, inhibition of glycolysis by 2-deoxyglucose has been reported to suppress activation of DCs. The aim of this study is to verify the effect of 3-bromopyruvate (BrPA), a specific inhibitor of HK2, on the differentiation and function of immune cells and on experimental arthritis in SKG mice.

Methods: Synovium from rheumatoid arthritis (RA) patients was stained by anti-HK2 antibody. Arthritis was induced in SKG mice by Zymosan A (ZyA) injection. BrPA (5mg/kg) was administered subcutaneously once daily. CD4+ T cells from spleens of unimmunized SKG mice were cultured with anti-CD3/anti-CD28, anti-IFN-γ, anti-IL-4, IL-6, TGF-β, IL-2, with and without BrPA for 5 days, and then analyzed by flow cytometry. Bone marrow (BM) cells from unimmunized SKG mice were cultured with GM-CSF and IL-4 (for 3 days), and with lipopolysaccharide (for 1 day) with and without BrPA, and then analyzed by flow cytometry.

Results: Immunohistochemistry revealed that HK2 expressing lymphocytes were increased in RA synovium. Treatment with BrPA significantly ameliorated arthritis of SKG mice (Figure). Histological scores of arthritis in BrPA-treated mice significantly were decreased compared to those of the control mice. Significant increase of Treg cells, decrease of Th17 cells, and decrease of CD40+CD86+CD11b+CD11c+ (activated) DCs were observed in the spleens from BrPA-treated SKG mice. In vitro, BrPA facilitated the differentiation of Treg cells, while it inhibited the development of Th17 cells. In addition, treatment of BM cells with BrPA reduced the proportion of activated DCs and inhibited the production of TNF-α, IL-6.

Conclusion: BrPA ameliorates autoimmune arthritis in SKG mice by facilitating the differentiation of Treg cells, and inhibiting the development of Th17 cells and activation of DCs.

Disclosure: T. Okano, None; J. Saegusa, None; K. Nishimura, None; Y. Ueda, None; S. Sendo, None; S. Takahashi, None; K. Akashi, None; A. Onishi, None; A. Morinobu, None.

To cite this abstract in AMA style:

Okano T, Saegusa J, Nishimura K, Ueda Y, Sendo S, Takahashi S, Akashi K, Onishi A, Morinobu A. Dual Effect of 3-Bromopyruvate on Both Th17 and Treg Cell Differentiation and Dendritic Cell Activation Ameliorates Autoimmune Arthritis in Mice [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/dual-effect-of-3-bromopyruvate-on-both-th17-and-treg-cell-differentiation-and-dendritic-cell-activation-ameliorates-autoimmune-arthritis-in-mice/. Accessed .

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