HECTD3 promotes NLRP3 inflammasome and pyroptosis to exacerbate diabetes-related cognitive impairment by stabilising MALT1 to regulate JNK pathway.

IF 4.7 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2024-08-01 Epub Date: 2022-08-01 DOI:10.1080/13813455.2022.2093377

Zhongfan Ruan, Yan Li, Yanfang Chen

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Abstract

Background: HECTD3 (HECT domain E3 ubiquitin protein ligase 3) exerts biological activities in neuroinflammation of distinct diseases, such as autoimmune encephalomyelitis and donations after heart death. However, the effect of HECTD3 on diabetes-associated cognitive decline (DACD) remains unclear.

Methods: Wild-type or HECTD3-knockout rats were administered with streptozotocin to establish diabetic model. Pathological changes in the hippocampus were assessed by NISSL and haematoxylin and eosin staining. Morris water maze test was used to assess cognitive function. Neuronal survival and inflammation were investigated by immunofluorescence staining and ELISA assay. NLRP3 inflammasome and pyroptosis were assessed by western blot, immunofluorescence and flow cytometry assays.

Results: HECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12 cells. Knockout of HECTD3 increased the number of neurons and improved the learning and memory function. Moreover, knockout of HECTD3 promoted in vivo neuronal survival, and reduced levels of IL-1β, TNF-α, and IL-6 in the hippocampus. Silencing of HECTD3 increased cell viability, and reduced IL-1β, TNF-α, and IL-6 in high glucose-induced PC12 cells. Fluorescence intensities of NLRP3, GSDMD-N and caspase-1 were reduced in HECTD3-knockout diabetic rats, and knockdown of HECTD3 down-regulated protein expression of NLRP3, GSDMD-N, caspase-1, IL-1β, and IL-18 in high glucose-induced PC12 cells to suppress the pyroptosis. HECTD3 promoted the stability of mucosa-associated lymphoid tissue 1 (MALT1) through up-regulation of c-JUN and phospho (p)-JNK in high glucose-induced PC12 cells. Over-expression of MALT1 attenuated neuroprotective effects of HECTD3 silencing on high glucose-induced PC12 cells.

Conclusion: HECTD3 silencing exerted neuroprotective effect against DACD through MALT1-mediated JNK signalling.HighlightsHECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12.Knockout of HECTD3 promoted in vivo neuronal survival, reduced inflammation and pyroptosis, and improved the learning and memory function in diabetic rats.Knockout of HECTD3 suppressed the activation of NLRP3 inflammasome in diabetic rats.Silencing of HECTD3 exerted neuroprotective effects through MALT1-mediated JNK signalling.

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HECTD3通过稳定MALT1以调控JNK通路，促进NLRP3炎性体和脓毒症，从而加剧糖尿病相关认知障碍。

背景：HECTD3（HECT domain E3 ubiquitin protein ligase 3）在自身免疫性脑脊髓炎和心脏死亡后捐赠等不同疾病的神经炎症中发挥生物活性。然而，HECTD3对糖尿病相关认知能力下降（DACD）的影响仍不清楚：方法：给野生型或 HECTD3 基因剔除大鼠注射链脲佐菌素，建立糖尿病模型。方法：给野生型大鼠或HECTD3基因剔除大鼠注射链脲佐菌素，建立糖尿病模型，通过NISSL和血苏木精及伊红染色评估海马的病理变化。莫里斯水迷宫测试用于评估认知功能。通过免疫荧光染色和酶联免疫吸附试验研究了神经元的存活和炎症情况。通过Western印迹、免疫荧光和流式细胞术检测NLRP3炎性体和炎症反应：结果：HECTD3在链脲佐菌素诱导的糖尿病大鼠海马和高糖诱导的PC12细胞中上调。敲除 HECTD3 能增加神经元数量，改善学习和记忆功能。此外，敲除HECTD3能促进体内神经元存活，并降低海马中IL-1β、TNF-α和IL-6的水平。在高糖诱导的PC12细胞中，沉默HECTD3可提高细胞存活率，降低IL-1β、TNF-α和IL-6水平。敲除HECTD3的糖尿病大鼠NLRP3、GSDMD-N和caspase-1的荧光强度降低，敲除HECTD3可下调高糖诱导的PC12细胞中NLRP3、GSDMD-N、caspase-1、IL-1β和IL-18的蛋白表达，从而抑制细胞的热解。在高糖诱导的 PC12 细胞中，HECTD3 通过上调 c-JUN 和 phospho (p)-JNK 促进了粘膜相关淋巴组织 1（MALT1）的稳定性。MALT1的过度表达削弱了HECTD3沉默对高糖诱导的PC12细胞的神经保护作用：摘要HECTD3在链脲佐菌素诱导的糖尿病大鼠和高糖诱导的PC12的海马中上调。敲除HECTD3可促进糖尿病大鼠体内神经元的存活，减少炎症和细胞凋亡，改善其学习和记忆功能；敲除HECTD3可抑制糖尿病大鼠NLRP3炎性体的激活；沉默HECTD3可通过MALT1介导的JNK信号发挥神经保护作用。

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来源期刊

ACS Applied Bio Materials Chemistry-Chemistry (all)

CiteScore

9.40

自引率

2.10%

发文量

464

期刊介绍： ACS Applied Bio Materials is an interdisciplinary journal publishing original research covering all aspects of biomaterials and biointerfaces including and beyond the traditional biosensing, biomedical and therapeutic applications. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrates knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important bio applications. The journal is specifically interested in work that addresses the relationship between structure and function and assesses the stability and degradation of materials under relevant environmental and biological conditions.