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

IF 4.8 2区 医学 Q2 IMMUNOLOGY
Yujiao Chen , Min Chen , Huifang Chen , Jin-hong Zhu , Chanyang Liang , Sijie Wu , Suda Gu , Weimin Sun , Jie Yan
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引用次数: 0

Abstract

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.
结肠上皮细胞坏死信号和 NLRP3 炎症小体的串联模式及其在结肠炎中的初始作用
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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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