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

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Title: Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β.
Authors: Hua MY; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Huang S; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Zhuang ZY; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China.; Department of Endocrinology and Metabolism, The First People's Hospital of Jinan, Jinan, 250011, China., Han XL; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Liu XJ; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Liang ZH; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Lou NJ; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Zheng FJ; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Lv L; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China., Zhuang XH; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China. zhuangxianghua@email.sdu.edu.cn.; Multidisciplinary Innovation Center for Nephrology of the Second Qilu Hospital of Shandong University, Jinan, 250033, China. zhuangxianghua@email.sdu.edu.cn., Yu SY; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. shuyanyu@sdu.edu.cn., Chen SH; Department of Endocrinology and Metabolism, The Second Qilu Hospital of Shandong University, Jinan, 250033, China. chenshihong@sdu.edu.cn.; Multidisciplinary Innovation Center for Nephrology of the Second Qilu Hospital of Shandong University, Jinan, 250033, China. chenshihong@sdu.edu.cn.
Source: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2026 Aug; Vol. 47 (8), pp. 2049-2064. Date of Electronic Publication: 2026 Mar 20.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE
Imprint Name(s): Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-
MeSH Terms: NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism , Pyroptosis*/physiology , Interleukin-1beta*/metabolism , Microglia*/metabolism , Hippocampus*/metabolism , Hippocampus*/pathology , Neurogenesis*/physiology , Cognitive Dysfunction*/metabolism , Cognitive Dysfunction*/etiology , Brain Diseases*/metabolism , Diabetes Complications*/metabolism, Caspase 1/metabolism ; Animals ; Mice, Inbred C57BL ; Male ; Mice ; Hypoglycemia
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.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Contributed Indexing: Keywords: IL-1β; NLRP3 inflammasome; adult hippocampal neurogenesis; cognitive dysfunction; diabetic encephalopathy; pyroptosis
Substance Nomenclature: 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Interleukin-1beta)
0 (Nlrp3 protein, mouse)
EC 3.4.22.36 (Caspase 1)
0 (IL1B protein, mouse)
SCR Disease Name: hypoglycemic encephalopathy
Entry Date(s): Date Created: 20260321 Date Completed: 20260721 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13388980
DOI: 10.1038/s41401-026-01774-0
PMID: 41862685
Database: MEDLINE
Description
ISSN:1745-7254
DOI:10.1038/s41401-026-01774-0