张华莉

教授 博士生导师 硕士生导师

入职时间:1997-07-09

所在单位:基础医学院

学历:博士研究生毕业

办公地点:湘雅老校区第二教学楼5楼

性别:女

联系方式:15607310187

学位:医学博士学位

在职信息:在职

主要任职:湖南省脓毒症转化医学重点实验室学术委员会副主任,湖南省病理生理学会副理事长,危重病专业委员会副主任委员,中国病理生理学会常务理事

毕业院校:中南大学

学科:基础医学

曾获荣誉:

2013-06-01  当选:  中南大学“升华学者”特聘教授

2013-06-01  当选:  湖南省自然科学杰出青年基金获得者

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LDK378 inhibits the recruitment of myeloid derived suppressor cells to spleen via the p38/GRK2/CCR2 pathway in mice with sepsis.

发布时间:2021-06-02

点击次数:

影响因子:3.745

发表刊物:Immunol Cell Biol.

关键字:CCR2, LDK378, myeloid-derived suppressor cells, sepsis

摘要:Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that are persistently increased in abundance and associated with adverse clinical outcomes in sepsis. Here, we investigated the therapeutic potential of an anaplastic lymphoma kinase inhibitor, LDK378, in cecal ligation and puncture (CLP)-induced polymicrobial sepsis and examined its effects on the recruitment of MDSCs. LDK378 significantly improved the survival of CLP-induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen. Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP-mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs. Mechanistically, LDK378 treatment blocked the CLP-induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G-protein-coupled receptor kinase-2 (GRK2) in bone marrow MDSCs of septic mice. Furthermore, in vitro experiments also showed that lipopolysaccharide (LPS)-induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS-induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration. Together, these findings unravel a novel function of LDK378 in the host response to infection and suggest that LDK378 could be a potential therapeutic agent for sepsis.

合写作者:Yanjuan Liu,Yang Yang,Chuyi Tan,Xue Wei,Yufang Wang,Sipin Tan,Meidong Liu,Ke Liu ,Ying Liu

第一作者:Jie Hu,Wenqin Zhang

论文类型:基础研究

通讯作者:Huali Zhang(通讯作者),Xianzhong Xiao

期号:2019 Nov;97(10):902-915.

是否译文:

发表时间:2019-08-29

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