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
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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：否
发表时间：2019-08-29