Background/Purpose

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that are characterized by the co-expression of Gr1 and CD11b in mice. MDSCs suppress T cell responses by producing arginase I (Arg I) and inducible nitric oxide synthase (iNOS). Tofacitinib is a Janus kinase (JAK) inhibitor that inhibits JAK1 and JAK3. Tofacitinib currently represents a novel therapeutic for treating rheumatoid arthritis. However, the anti-rheumatic effects of tofacitinib, especially its influence on myeloid cells, are not fully understood. The aim of this study was to evaluate the effects of the Janus kinase inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis.

Methods

Arthritis was induced in SKG mice by zymosan A (ZyA) injection. MDSCs isolated from the bone marrow (BM) of donor arthritic SKG mice were adoptively transferred to recipient arthritic mice. In a separate experiment, tofacitinib was administered to SKG arthritic mice subcutaneously via osmotic pump, in some cases followed by injection of an anti-Gr1 monoclonal antibody (mAb). BM cells from untreated mice were cultured for 5 days with granulocyte/macrophage colony-stimulating factor (GM-CSF), with or without tofacitinib, and then analyzed by flow cytometry.

Results

The BM and spleens of ZyA-treated mice contained increased numbers of CD11b⁺Gr1⁺ MDSCs, whereas polymorphonuclear (PMN)-MDSCs (CD11b⁺Ly6G⁺Ly6C^low) were significantly increased in the spleen of ZyA-treated mice. The number of monocytic-MDSCs (CD11b⁺Ly6G^–Ly6C^high) was also significantly increased in the BM of ZyA-treated mice, although they represented only a small proportion of the BM cells. The BM cells from ZyA-treated SKG mice also expressed higher levels of iNOS and Arg I compared to untreated SKG mice. The adoptive transfer of MDSCs to recipient arthritic mice reduced disease severity compared to the untreated controls. Continuous administration of tofacitinib significantly ameliorated the arthritic scores of SKG mice. Tofacitinib treatment significantly increased the numbers of total- and PMN-MDSCs in the BM of arthritic mice. Furthermore, the anti-arthritic effect of tofacitinib was abrogated when MDSCs were depleted by anti-Gr1 mAb. In vitro, tofacitinib facilitated the differentiation of BM cells to MDSCs, and inhibited their differentiation to dendritic cells. Moreover, tofacitinib-treated BM cells were incapable of enhancing T cell proliferation, compared to mock-treated BM cells.

Conclusion

MDSCs play crucial roles in the regulation of SKG arthritis, and a JAK inhibitor, tofacitinib, enhances their expansion. Our results suggest a novel mode of anti-arthritic action for tofacitinib and a critical role for JAKs in the differentiation of MDSCs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-facilitates-the-expansion-of-myeloid-derived-suppressor-cells-and-ameliorates-arthritis-in-skg-mice/