在饮食诱发肥胖的小鼠模型中，肠胶质 NLRP3 炎症小体有助于肠道粘膜屏障的改变

IF 8.3 2区材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Materials & Interfaces Pub Date : 2024-09-17 DOI:10.1111/apha.14232

Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini

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Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3−/− mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. 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引用次数: 0

摘要

方法用高脂饮食（HFD）或标准饮食喂养野生型 C57BL/6J 和 NLRP3-KO (-/-) 小鼠 8 周。对结肠IEB完整性和炎性体活化进行了评估。结肠粘膜 GFAP 和 NLRP3 阳性细胞的免疫定位以及肠胶质细胞（EGCs）和 IECs 的体外共培养实验有助于研究 IEB 改变、肠胶质病变和 NLRP3 激活之间的潜在联系。HFD-NLRP3-/-小鼠的体重增幅较小，IEB完整性有所改善，并且没有出现肠胶质病变。共培养实验表明，棕榈酸酯和脂多糖会导致IEB损伤，并促进肠胶质细胞病变，从而导致肠胶质细胞NLRP3/caspase-1/IL-1β信号超活化。源于肠胶质的IL-1β释放会加剧IEB的改变。结论高脂血症摄入会引起粘膜肠胶质过程，其特点是 NLRP3/caspase-1/IL-1β信号通路过度激活，从而进一步加剧肠粘膜屏障完整性的破坏。然而，我们不能排除其他细胞（如免疫细胞）激活 NLRP3 炎性体对肥胖相关的 IEB 改变的贡献。总之，我们的研究结果表明，肠胶质 NLRP3 炎症小体可能是一个有趣的分子靶点，可用于开发新型药理方法，以控制与肥胖相关的肠道炎症和肠粘膜功能障碍。

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Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet‐induced obesity

AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (−/−) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3−/− mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.

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来源期刊

ACS Applied Materials & Interfaces 工程技术-材料科学：综合

CiteScore

16.00

自引率

6.30%

发文量

4978

审稿时长

1.8 months

期刊介绍： ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.