(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway
(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway
复制标题
( )-冰片通过 JAK2-STAT3 信号通路促进 M2 巨噬细胞极化，提高依达拉奉对抗 DSS 诱导的结肠炎的功效
DOI：
10.1016/j.intimp.2017.10.002
复制
发表时间：
2017-12-01
影响因子：
5.6
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Zhang, Xiong;Xu, Fang;Xu, Qiang
复方依达拉奉注射液（C.EDA）是由依达拉奉（EDA）与（+）-冰片按质量比4:1组成的复方制剂，其抗炎活性优于依达拉奉。然而，其确切机制仍有待进一步研究。在本研究中，我们探究了（+）-冰片是否能提高依达拉奉对葡聚糖硫酸钠（DSS）诱导的结肠炎的疗效。我们发现，7.5和15毫克/千克的C.EDA能以剂量依赖的方式显著缓解疾病活动指数（DAI），减轻体重下降并减少结肠长度缩短，而单独使用依达拉奉或（+）-冰片即使在最高剂量下也仅产生中等程度的效果。此外，酶联免疫吸附试验（ELISA）显示，与单独使用依达拉奉或（+）-冰片相比，C.EDA在结肠组织和血清中能更显著地降低炎症细胞因子的蛋白水平，并提高抗炎细胞因子的水平。苏木精 - 伊红（H&E）染色和免疫组化分析也表明，C.EDA在增加M2型巨噬细胞数量、减少M1型巨噬细胞浸润以及保护肠道屏障完整性方面表现出更显著的效果。此外，体外研究表明，C.EDA、依达拉奉或（+）-冰片均不能抑制M1型巨噬细胞的激活，但能以信号转导及转录激活因子3（STAT3）依赖的方式特异性诱导M2型巨噬细胞的激活。敲低STAT3的表达成功消除了C.EDA和依达拉奉对促进M2型巨噬细胞激活的作用。与体内研究一致，在体外，C.EDA比单独使用依达拉奉或（+）-冰片更能有效地诱导M2型巨噬细胞极化和STAT3激活。总之，我们证实（+）-冰片通过JAK2 - STAT3信号通路促进M2型巨噬细胞极化，从而提高了依达拉奉对DSS诱导的结肠炎的疗效。
Compound edaravone injection (C.EDA), a compound preparation composed of edaravone (EDA) and (+)-Borneol with the mass ratio of 4: 1, displays a better anti-inflammatory activity than EDA. However, its precise mechanism remains to be further studied. In this work, we investigated whether (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis. We found that C.EDA at 7.5 and 15 mg/kg could significantly relieve the disease activity index (DAI) and reduce the loss of body weight and colon length in a dose-dependent manner, while EDA or (+)-Borneol alone only had moderate effects even at the highest dose. Additionally, ELISA revealed that C.EDA could more dramatically decrease the protein levels of inflammatory cytokines and increase the levels of anti-inflammatory cytokine than EDA or (+)-Borneol alone both in colon tissues and serum. H&E staining and IHC assay also indicated that C.EDA exhibited more prominent effects on increasing the population of M2 macrophages, decreasing M1 macrophages infiltration and protecting intestinal barrier integrity. Furthermore, in vitro studied demonstrated that C.EDA, EDA or (+)-Borneol failed in inhibiting M1 macrophages activation but could specifically induce the activation of M2 macrophages in a STAT3-dependent manner. Knockdown the expression of STAT3 successfully abolished the effect of C.EDA and EDA on promoting M2 macrophages activation. Consistent with in vivo study, C.EDA exhibited a more efficient ability of inducing M2 macrophages polarization and STAT3 activation than EDA or (+)-Borneol alone in vitro. In conclusion, we confirmed that (+)-Borneol improved the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.