MLKL attenuates colon inflammation and colitis-tumorigenesis via suppression of inflammatory responses
MLKL attenuates colon inflammation and colitis-tumorigenesis via suppression of inflammatory responses
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MLKL 通过抑制炎症反应减轻结肠炎症和结肠炎肿瘤发生
DOI：
10.1016/j.canlet.2019.05.034
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发表时间：
2019
期刊：
影响因子：
9.7
通讯作者：
Zhang Haibing
中科院分区：
文献类型：
--
作者：
Zhao Qun;Yu XianJun;Li Ming;Liu YongBo;Han YaMei;Zhang XiXi;Li Xiao Ming;Wu XiaoXia;Qin Jun;Fang Jing;Zhang Haibing
混合谱系激酶结构域样蛋白（MLKL）已成为坏死性凋亡的关键介质，其导致细胞损伤相关分子模式（DAMP）的释放。然而，其在调节炎症中的生理作用尚未完全了解。我们在此发现Mlkl −/−小鼠对结肠炎和结肠炎相关肿瘤发生（CAT）高度易感，这与大量白细胞浸润和炎症反应增加有关。此外，我们使用骨髓移植来揭示炎症细胞中的MLKL对于其在结肠炎中的作用至关重要。从Mlkl −/−小鼠中分离的肠粘膜组织和息肉表现出ERK活化增加以及与炎症和癌症相关的基因表达升高。从机制上讲，Mlkl −/−小鼠中增强的炎症是由于MEK/ERK激活，特别是在树突状细胞（DC）中。我们的研究结果证明了MLKL在维持肠道内环境稳定和预防结肠炎和肿瘤发生中的作用。
The mixed lineage kinase domain-like protein (MLKL) has emerged as a critical mediator of necroptosis, which results in the release of cellular damage-associated molecular patterns (DAMPs). However, its physiological role in regulating inflammation is not fully understood. We herein showed thatMlkl−/−mice were highly susceptible to colitis and colitis-associated tumorigenesis (CAT), which was associated with massive leukocyte infiltration and increased inflammatory responses. Moreover, we used bone marrow transplantation to reveal that MLKL in inflammatory cells is crucial for its role on colitis. Intestinal mucosal tissue and polyps isolated fromMlkl−/−mice exhibited increased ERK activation and elevated expression of genes associated with inflammation and cancer. Mechanistically, enhanced inflammation inMlkl−/−mice was due to MEK/ERK activation particularly in dendritic cells (DCs). Our results demonstrate the role of MLKL in maintaining intestinal homeostasis and protecting against colitis and tumorigenesis.