Crosstalk patterns of necroptosis signaling and NLRP3 inflammasome in the colonic epithelium and its initial role in colitis.

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Tác giả: Huifang Chen, Min Chen, Yujiao Chen, Suda Gu, Chanyang Liang, Weimin Sun, Sijie Wu, Jie Yan, Jin-Hong Zhu

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: Netherlands : International immunopharmacology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 713611

Inflammation-mediated epithelial damage, including necroptosis of the intestinal epithelia, can lead to subsequent immune responses, but the molecular mechanisms of inflammation in the initial stages are not well understood. Based on cellular experiments and mouse models, we investigated the activation of the NLRP3 inflammasome under necroptotic conditions, and its contribution to the inflammatory response in colitis. Our results showed that, under inflammatory conditions, intestinal epithelial cells (IECs) undergo phosphor-MLKL-dependent necroptosis with subsequent activation of the NLRP3 inflammasome for caspase-1 activation and IL-1β maturation. Mechanisms investigation revealed that components of the inflammasome were primed through the NF-κB signaling pathway and ASC-NLRP3 organization was dependent on mitochondrial reactive oxygen species (ROS), which could be promoted by necroptosis signaling. In addition, we found that Tempol, a kind of compound for ROS neutralization, could effectively reduce intestinal inflammation in mice by inhibiting the activation of the NLRP3 pathway in epithelia. Taken together, our research suggests that the necroptosis-triggered NLRP3 inflammasome in IECs plays an important role in the initiation of epithelial shedding and further inflammatory response in colitis. Our results provide a novel insight into the use of the ROS inhibitor Tempol as a treatment for the prevention of immune response and inflammation-induced tissue damage in the intestinal epithelium and thus as a potential therapeutic target for IBD.
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