The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis.

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2023-10-27 DOI:10.1186/s12929-023-00983-7
Valentina Arrè, Rosanna Scialpi, Matteo Centonze, Gianluigi Giannelli, Maria Principia Scavo, Roberto Negro
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Abstract

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.

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NLRP3焦下垂通路在胃肠道炎症性疾病和肿瘤发生中的“斑点”-触觉监督。
NLRP3炎症小体是一种细胞内传感器,也是参与危险识别的先天免疫系统的重要组成部分。炎症小体激活的一个重要标志是每个细胞形成一个被称为斑点的超分子点,这是促炎细胞因子IL-1β和IL-18转化为其生物活性形式的位点。斑点还为gasdermin D蛋白激活提供了平台,其N末端结构域穿过质膜,允许成熟细胞因子的释放以及高度炎症形式的细胞死亡,即pyroptosis。尽管受控的NLRP3炎症小体-肥大途径激活可保持粘膜免疫稳态并有助于宿主防御,但长期触发是有害的,并可能导致遗传易感性受试者患上炎症性肠病,包括克罗恩病和溃疡性结肠炎,以及胃肠道癌症。实验证据表明,NLRP3炎症小体具有保护和致病能力。在这篇综述中,我们强调了NLRP3焦下垂轴在分子水平上对胃肠道病理生理学的影响,重点是新发现的具有促炎、抗炎和肿瘤活性的特征,以及在临床前和临床试验中测试的靶向疗法。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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