Department of Geriatrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Am J Physiol Cell Physiol. 2024 Dec 1;327(6):C1481-C1496. doi: 10.1152/ajpcell.00322.2024. Epub 2024 Oct 22.
Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The cross talk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high-glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were used to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. In addition, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE. This article delves into the intricate connections between inflammation, autophagy, diabetes, and neurodegeneration, with a particular focus on a disease that is not yet fully understood-diabetic encephalopathy (DE). TFEB emerges as a pivotal regulator in balancing autophagy and inflammation in DE. Our findings highlight the crucial function of the TFEB-mediated autophagy pathway in mitigating inflammatory damage in DE, suggesting a new treatment strategy.
糖尿病性脑病（DE）是糖尿病的一种神经并发症，其病因尚不清楚。有大量证据表明，核苷酸结合寡聚化结构域样受体家族蛋白 3（NLRP3）炎性小体诱导的神经炎症和转录因子 EB（TFEB）介导的自噬损伤可能参与了 DE 的发生发展。这两种途径之间的相互作用及其对 DE 的贡献仍有待探索。我们构建了一种伴有认知功能障碍的 2 型糖尿病（T2DM）小鼠模型，并培养了高糖（HG）BV2 细胞。然后，我们使用 3-甲基腺嘌呤（3-MA）和雷帕霉素来调节自噬。为了评估 TFEB 在 DE 中的潜在治疗益处，我们在小鼠和细胞中过表达和敲低了 TFEB。在 T2DM 小鼠和 HG 培养的 BV2 细胞中，观察到自噬损伤和 NLRP3 炎性小体激活。雷帕霉素诱导的自噬增强降低了 NLRP3 炎性小体激活引起的炎症反应，而 3-MA 处理则进一步恶化了这种反应。HG 培养的 BV2 细胞和 T2DM 小鼠中 TFEB 的核转位和表达受到阻碍。外源性 TFEB 过表达通过自噬促进 NLRP3 的降解，从而减轻小胶质细胞的激活，并改善认知缺陷和神经元损伤。此外，TFEB 敲低通过降低自噬介导的 NLRP3 降解来加重神经炎症。我们的研究结果揭示了一种以前未被充分认识的疾病的发病机制，表明小胶质细胞中 NLRP3 炎性小体的激活和自噬的损伤是 DE 的重要病因。TFEB 介导的自噬途径可以通过增强 NLRP3 的降解来减少神经炎症。这可能成为 DE 的一种可行的创新治疗方法。本文深入探讨了炎症、自噬、糖尿病和神经退行性变之间的复杂联系，特别关注一种尚未完全了解的疾病——糖尿病性脑病（DE）。TFEB 作为 DE 中自噬和炎症平衡的关键调节剂出现。我们的研究结果强调了 TFEB 介导的自噬途径在减轻 DE 中炎症损伤方面的关键作用，为 DE 提供了一种新的治疗策略。
