Lipin2 ameliorates diabetic encephalopathy via suppressing JNK/ERK-mediated NLRP3 inflammasome overactivation

Xiaochen Zhang; Shan Huang; Ziyun Zhuang; Xiaolin Han; Min Xie; Shuyan Yu; Mengyu Hua; Zhonghao Liang; Chao Meng; Ling Yin; Xianghua Zhuang; Shihong Chen

doi:10.1016/j.intimp.2023.109930

Lipin2 ameliorates diabetic encephalopathy via suppressing JNK/ERK-mediated NLRP3 inflammasome overactivation

Int Immunopharmacol. 2023 May:118:109930. doi: 10.1016/j.intimp.2023.109930. Epub 2023 Mar 29.

Authors

Xiaochen Zhang¹, Shan Huang², Ziyun Zhuang³, Xiaolin Han², Min Xie⁴, Shuyan Yu⁵, Mengyu Hua², Zhonghao Liang², Chao Meng⁶, Ling Yin⁷, Xianghua Zhuang⁸, Shihong Chen⁹

Affiliations

¹ Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Department of Clinical Medicine, Heze Medical College, Heze 274009, China.
² Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China.
³ Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Department of Endocrinology and Metabolism, First People's Hospital of Jinan, Jinan 250011, China.
⁴ Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou 256603, China.
⁵ Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
⁶ Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China; Department of Endocrinology and Metabolism, Jinan Central Hospital, Jinan 250013, China.
⁷ Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250098, China.
⁸ Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China. Electronic address: sd73095760653@163.com.
⁹ Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan 250033, China. Electronic address: chenshihong26@163.com.

PMID: 37001383
DOI: 10.1016/j.intimp.2023.109930

Abstract

Objectives: Diabetic encephalopathy (DE) is a common complication of diabetes in the central nervous system, which can cause cognitive dysfunction in patients. However, its pathophysiological mechanism has not been elucidated, and thus effective prevention and treatment methods are still lacking.Previous studies reported that neuroinflammation involved in the central neuropathy, while lipin2 plays an important role in inflammatory response.Therefore, we aimed to investigate the effects of lipin2 on regulating inflammatory response in the pathogenesis of DE.

Methods: BV2 cells were treated with high glucose and infected with lipin2 overexpression or knockdown virus to observe the cell viability. Then, we constructed a mouse model of DE, and constructed a lipin2 knockdown or overexpression model by injecting lentivirus into the brain with stereotaxis. The expression of lipin2 in inflammatory bodies and related inflammatory factor signaling pathway-related proteins were examined by western blot and quantitative real-time PCR. Morris water maze was used to evaluate the spatial learning and memory of mice.

Results: High glucose decreased the expression of lipin2 in BV2 cells, while overexpression of lipin2 in BV2 cells significantly suppressed the inflammatory response and apoptosis induced by high glucose. Meanwhile, the expression of lipin2 was down-regulated in the hippocampus in a DE mice model. Up-regulation of lipin2 in the hippocampus of DE mice inhibited JNK/ERK signaling pathway, reduced NLRP3 inflammasome-mediated inflammatory response, down-regulated IL-1/TNF-α expression, and improved synaptic plasticity and cognitive dysfunction in mice. Conversely, knockdown of lipin2 increased NLRP3 inflammasome overactivation, caused neuronal abnormalities and cognitive impairment in mice.

Conclusions: Lipin2 may play a neuroprotective role in DE by inhibiting JNK/ERK-mediated NLRP3 inflammasome overactivation and subsequent inflammatory responses. It may be a potential therapeutic target for DE therapy.

Keywords: Diabetic encephalopathy; JNK/ERK signaling pathway; Lipin2; NLRP3 inflammasome.

MeSH terms

Animals
Brain Diseases*
Diabetes Mellitus*
Disease Models, Animal
Glucose
Inflammasomes / metabolism
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Glucose
Nlrp3 protein, mouse

Supplementary concepts

hypoglycemic encephalopathy