Cell Rep|Mathilde Mathieu团队揭示TM4SF5依赖性相互作用重编程炎性环境的作用机制

2022年8月4日 0条评论 284次阅读 0人点赞

最新细胞功能及机制文献分享

肝细胞的慢性损伤会导致炎症、脂肪性肝炎、纤维化和非酒精性脂肪肝（NAFLD）的发生。四肽TM4SF5与纤维化和癌症有关。2021年11月16日，韩国首尔国立大学药学院药学科学研究所药学系Jung Weon Lee团队在Cell Reports上发表了题为“TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment”的研究论文。团队认为巨噬细胞（MΦs）和肝细胞中的TM4SF5表达在NAFLD进展过程中参与调节炎症环境，TM4SF5调节肝细胞和MΦs之间的双向通讯，其介导的炎症性MΦs重塑可促进NAFLD进展。

研究显示，与肝损伤相关的炎症可导致多种细胞因子和趋化因子的产生，而这加剧了恶性肿瘤、NASH和异常细胞外基质（ECM）的产生。存在于肝脏或来自单核细胞的MΦs在整个NAFLD进展过程中具有非炎性/炎性作用。因此，了解NAFLD发展过程中MΦs极化和炎症信号传导间的相互作用是十分重要的。由CCL2、CCL5以及TGF-b1诱导的TM4SF5参与肝纤维化和肝细胞癌的发生和发展。

在本研究中，团队通过构建体内小鼠模型和体外细胞培养体系，研究了TM4SF5介导的NAFLD进展过程中MΦs极化和MΦs与肝细胞之间的关系。着重探讨了TM4SF5在肝细胞和MΦs之间的通讯作用及其对NAFLD炎症微环境的影响。研究发现，TM4SF5可促进葡萄糖摄取、糖酵解和葡萄糖敏感性，导致M1型MΦs的激活，随后活化的M1型MΦs分泌促炎性IL-6，诱导TM4SF5阳性肝细胞分泌CCL20和CXCL10趋化因子。尽管这些趋化因子的TM4SF5依赖性分泌增强了M0型MΦ中的糖酵解，但也造成了MΦ的进一步重编程，导致M2型MΦ比例增加，支持了饮食和化学诱导的NAFLD进展。总之，团队认为在NAFLD的发展过程中，TM4SF5可介导肝细胞和巨噬细胞之间的相互作用，从而重塑炎症环境。机制上，TM4SF5依赖性互作涉及肝脏CCL20/CXCL10和MΦs对IL-6的分泌，导致促炎性MΦs的激活，这些MΦs可被慢性重编程，最终促进NAFLD进展。

《Cell Rep|Mathilde Mathieu团队揭示TM4SF5依赖性相互作用重编程炎性环境的作用机制》

图本文图形摘要示意图。

期刊及DOI号

Cell Rep. 2021 Nov 16.

doi: 10.1016/j.celrep.2021.110018.

题目

TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment

摘要

Chronic injury to hepatocytes results in inflammation, steatohepatitis, fibrosis, and nonalcoholic fatty liver disease (NAFLD). The tetraspanin TM4SF5 is implicated in fibrosis and cancer. We investigate the role of TM4SF5 in communication between hepatocytes and macrophages (MΦs) and its possible influence on the inflammatory microenvironment that may lead to NAFLD. TM4SF5 induction in differentiated MΦs promotes glucose uptake, glycolysis, and glucose sensitivity, leading to M1-type MΦ activation. Activated M1-type MΦs secrete pro-inflammatory interleukin-6 (IL-6), which induces the secretion of CCL20 and CXCL10 from TM4SF5-positive hepatocytes. Although TM4SF5-dependent secretion of these chemokines enhances glycolysis in M0 MΦs, further chronic exposure reprograms MΦs for an increase in the proportion of M2-type MΦs in the population, which may support diet-and chemical-induced NAFLD progression. We suggest that TM4SF5 expression in MΦs and hepatocytes is critically involved in modulating the inflammatory environment during NAFLD progression.