Inhibition of the Mechanistic Target of Rapamycin Pathway and Glutaminolysis Facilitates the Expansion of Myeloid-Derived Suppressor Cells and Synergistically Ameliorates Arthritis in SKG Mice

Yo Ueda¹, Takaichi Okano¹, Hirotaka Yamada¹, Yoshihide Ichise¹, Ikuko Naka², Soshi Takahashi³, Sho Sendo⁴, Kengo Akashi², Akira Onishi⁵, Jun Saegusa⁴ and Akio Morinobu³, ¹Department of Rheumatology and Clinical immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ²Kobe University Graduate School of Medicine, Kobe, Japan, ³Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ⁴Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, ⁵Rheumaology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Arthritis, mTor and metabolism

Session Information

Date: Monday, November 6, 2017

Title: Rheumatoid Arthritis – Animal Models Poster II

Session Type: ACR Poster Session B

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

Background/Purpose: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that increase in the pathological state such as tumor or inflammation and have the immunosuppressive ability. MDSCs have been reported to ameliorate arthritis in several mice models. The mechanistic target of rapamycin (mTOR) pathway and glutaminolysis are known to be activated in the differentiation from myeloid progenitors to mature myeloid cells such as dendritic cells, macrophages, or osteoclasts. The aim of this study is to evaluate the facilitative effects of the inhibition of mTOR pathway and glutaminolysis on MDSCs in a mouse model of rheumatoid arthritis.

Methods: Bone marrow (BM) cells from untreated Balb/c mice were cultured for 5 days under granulocyte–macrophage colony-stimulating factor (GM-CSF) stimulation with four patterns of drugs; 1) DMSO (control), 2) rapamycin, 3) 6-Diazo-5-oxo-L-norleucine (DON; a glutamine analogue), or 4) the combination of rapamycin and DON. Cultured BM cells were analyzed by flow cytometry. Cultured MDSCs were isolated by manual MACS and analyzed their immunosuppressive characters by co-culture with CFSE-dyed CD4+ T cells. The four patterns of drugs described above were administered intraperitoneally to arthritic SKG mice induced by Zymosan A injection.

Results: We found that DON administration (separately or in combination) significantly suppressed the differentiation from BM cells to dendritic cells in vitro. Most DON-treated BM cells showed the phenotype of MDSCs, large part of which were Ly6G+ cells (the phenotype of polymorphonuclear MDSCs; PMN-MDSCs). On the other hand, rapamycin administration (separately or in combination) significantly increased the TGF-b expression and the inhibitory capacity of Ly6G+ PMN-MDSCs. The combination of rapamycin and DON was the most effective to suppress arthritis in SKG mice among these four treatment patterns (see Fig 1).

Conclusion: The combination of rapamycin and DON facilitates the expansion of PMN-MDSCs in vitro and synergistically ameliorates arthritis in SKG mice in vivo.

Disclosure: Y. Ueda, None; T. Okano, None; H. Yamada, None; Y. Ichise, None; I. Naka, None; S. Takahashi, None; S. Sendo, None; K. Akashi, None; A. Onishi, None; J. Saegusa, None; A. Morinobu, None.

To cite this abstract in AMA style:

Ueda Y, Okano T, Yamada H, Ichise Y, Naka I, Takahashi S, Sendo S, Akashi K, Onishi A, Saegusa J, Morinobu A. Inhibition of the Mechanistic Target of Rapamycin Pathway and Glutaminolysis Facilitates the Expansion of Myeloid-Derived Suppressor Cells and Synergistically Ameliorates Arthritis in SKG Mice [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/inhibition-of-the-mechanistic-target-of-rapamycin-pathway-and-glutaminolysis-facilitates-the-expansion-of-myeloid-derived-suppressor-cells-and-synergistically-ameliorates-arthritis-in-skg-mice/. Accessed .

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