Background/Purpose: SKG mice, which are rheumatoid arthritis (RA) model, develop not only arthritis but interstitial lung disease (ILD) resembling RA-ILD. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with suppressive functions. We previously reported that tofacitinib, which is JAK inhibitor, facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice. The purpose of this study is to elucidate the effect of tofacitinib on ILD in SKG mice.

Methods: SKG mice were induced ILD by Zymosan A (ZyA) injection. Four weeks after the ZyA-injection, tofacitinib (20 mg/kg) or DMSO was intraperitoneally injected three times per week for eight weeks. We evaluated lung infiltrating cells by flow cytometry, and severity of ILD by HE staining. DC generation, T-cell proliferation and Th17 cell differentiation assays were performed in vitro.

Results: Tofacitinib significantly suppressed the progression of ILD compared to control. Flow cytometry revealed that tofacitinib significantly increased MDSCs and suppressed Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF⁺ILCs in vivo. Tofacitinib suppressed the Th17 cell differentiation and increased MDSCs expansion in vitro. MDSCs expanded in the inflamed lungs also suppressed T cell proliferation and Th17 cell differentiation ex vivo.

Discussion: To our knowledge, this is the first report to show that tofacitinib is effective for RA-ILD model. Tofacitinib not only directly but also indirectly suppress the pathogenic lymphocytes by facilitating the expansion of MDSCs. These results indicate a potential therapeutic effect of tofacitinib for RA-ILD.

Conclusion: Tofacitinib facilitates the expansion of MDSCs and suppresses Th17 cells, which in turn suppress the progression of ILD in SKG mice.