Abstract
BackgroundRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice.MethodsWe assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro.ResultsTofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro.ConclusionTofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice.
Highlights
Rheumatoid arthritis-associated interstitial lung disease (RA-Interstitial lung disease (ILD)) is a sometimes life-threatening complication in rheumatoid arthritis (RA) patients
Representative flow cytometry plots of myeloid-derived suppressor cells (MDSCs) from the lungs of control mice and tofacitinib-treated mice. b Comparison of the lung-infiltrating MDSCs in control mice (n = 5) versus tofacitinib-treated mice (n = 5). c Carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled CD4+ T cells were cultured for 3 days with CD3 and CD28 stimulation, with or without the indicated proportion of lung MDSCs obtained from Zym-injected SKG mice. d Representative flow cytometry plots of the Th17 cell differentiation assay
We previously reported that tofacitinib facilitates the expansion of MDSCs in the bone marrow (BM) and in the spleen and that it ameliorates arthritis in SKG mice [10], but we did not detect the expansion of MDSCs in the inflammatory site
Summary
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop arthritis and an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice. Interstitial lung disease (ILD) is sometimes a complication of rheumatoid arthritis (RA), in which case it is called rheumatoid arthritis-associated ILD (RA-ILD). Monocyte-derived suppressor cells (MDSCs) are immature myeloid cells with a suppressive function. MDSCs negatively control inflammation in inflamed organs such as the lungs and joints by suppressing T cells and myeloid cells [4, 5].
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