铁蛋白重亚基通过 ICAM-1 刺激肝星状细胞中的 NLRP3 炎症小体,从而驱动肝脏炎症

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm
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引用次数: 0

摘要

肝脏炎症时血清铁蛋白浓度会升高,并与慢性肝病的严重程度相关。在这里,我们报告了铁蛋白重亚基(FTH)促进肝脏炎症的分子机制。我们发现 FTH 通过细胞间粘附分子-1(ICAM-1)诱导原代大鼠肝星状细胞(HSCs)激活 NLRP3 炎性体并分泌促炎细胞因子白细胞介素-1β(IL-1β)。FTH-ICAM-1刺激了Il1b的表达、NLRP3炎性体的激活以及IL-1β的加工和分泌,其方式依赖于质膜重塑、凝胶酶介导的内吞和溶酶体失稳。早期内体的FTH-ICAM-1信号刺激了Il1b的表达,这意味着这种内体信号激活了造血干细胞中的炎性体。相反,溶酶体失稳是FTH诱导IL-1β分泌的必要条件,这表明溶酶体损伤激活了炎性体。FTH能诱导野生型小鼠肝切片产生IL-1β,但不能诱导Icam1-/-或Nlrp3-/-小鼠肝切片产生IL-1β。因此,FTH通过造血干细胞上的受体ICAM-1发出信号,激活NLRP3炎性体。我们推测这一途径有助于肝脏炎症,而肝脏炎症是刺激与慢性肝病相关的肝纤维化的关键过程。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation
Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1−/− or Nlrp3−/− mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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