2. Academic Validation
  3. Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β

Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β

  • Acta Pharmacol Sin. 2026 Mar 20. doi: 10.1038/s41401-026-01774-0.
Meng-Yu Hua # 1,  Shan Huang # 1,  Zi-Yun Zhuang 1 2,  Xiao-Lin Han 1,  Xiao-Jing Liu 1,  Zhong-Hao Liang 1,  Neng-Jun Lou 1,  Feng-Jie Zheng 1,  Li Lv 1,  Xiang-Hua Zhuang 3 4,  Shu-Yan Yu 5,  Shi-Hong Chen 6 7
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China.
  • 2 Department of Endocrinology and Metabolism, The First People's Hospital of Jinan, Jinan, 250011, China.
  • 3 Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 4 Multidisciplinary Innovation Center for Nephrology of the Second Qilu Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 5 Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. [email protected].
  • 6 Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 7 Multidisciplinary Innovation Center for Nephrology of the Second Qilu Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • # Contributed equally.
PMID: 41862685 DOI: 10.1038/s41401-026-01774-0
Abstract

Diabetic encephalopathy (DE) is a prevalent complication of diabetes which can lead to cognitive dysfunction, without effective therapy currently. In diabetic patients, a reduction in adult hippocampal neurogenesis (AHN) is a heightened risk of cognitive impairment, which may be associated with neuroinflammation caused by microglia. In this study, we established a DE mouse model and conducted in vitro cultures of microglial cells and neural stem cells. Our study demonstrated that the high-glucose associated with DE impairs AHN and induces microglial NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) dependent Pyroptosis. Further investigation showed that upregulation of microglial NLRP3 promotes the activation of Gasdermin D (GSDMD), the key Pyroptosis effector, and the cleavage of pro-interleukin-1β (pro-IL-1β) by Caspase-1, exacerbated Pyroptosis and induced release of IL-1β, which might lead to impaired AHN and subsequent cognitive dysfunction. Conversely, downregulation of microglial NLRP3 inhibited Caspase-1 activation and Pyroptosis, reduced release of IL-1β, improved AHN, and rescued cognitive deficits in DE mouse model. Such findings suggest that targeting microglial NLRP3 inflammasome-mediated Pyroptosis may be an important potential therapeutic target for treating DE.

Keywords

IL-1β; NLRP3 inflammasome; adult hippocampal neurogenesis; cognitive dysfunction; diabetic encephalopathy; pyroptosis.

Figures
Products