Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice
Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice
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DOI：
10.1186/s13075-019-1963-2
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发表时间：
2019-08-06
影响因子：
4.9
通讯作者：
Morinobu, Akio
中科院分区：
文献类型：
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作者：
Sendo, Sho;Saegusa, Jun;Morinobu, Akio
背景风湿性关节炎相关间质性肺疾病（RA-ILD）是RA患者有时危及生命的并发症。SKG小鼠不仅发生关节炎，还发生类似RA-ILD的ILD。我们以前报道过，托法替尼，JAK抑制剂，促进骨髓源性抑制细胞（MDSC）的扩增，并改善SKG小鼠的关节炎。本研究旨在阐明托法替尼对SKG小鼠ILD的影响。方法采用酵母多糖（zymosan，Zym）诱导的SKG小鼠ILD模型，观察托法替尼对小鼠肺组织病理学的影响，并采用流式细胞术检测肺组织浸润细胞。在体外评估肺MDSCs对T细胞增殖和Th 17细胞分化的影响。我们还在体外评估了托法替尼对MDSC和树突状细胞的影响。结果与对照组相比，托法替尼能显著抑制SKG小鼠ILD的进展。托法替尼给药小鼠肺中MDSC增加，而Th 17细胞、第1组先天淋巴样细胞（ILC 1）和GM-CSF+ILCs减少。从发炎的肺中分离的MDSC在体外抑制T细胞增殖和Th 17细胞分化。托法替尼在体外促进MDSC扩增并抑制骨髓来源的树突状细胞（BMDC）分化。结论托法替尼可促进SKG小鼠MDSC在肺内的扩增，改善ILD。
Background Rheumatoid 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. Methods We 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. Results Tofacitinib 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. Conclusion Tofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice.