Imeglimin Exhibits Novel Anti-Inflammatory Effects on High-Glucose-Stimulated Mouse Microglia Through ULK1-Mediated Suppression of the TXNIP-NLRP3 Axis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Feb 9

PMID 38334676

Authors

Hisashi Kato

Kaori Iwashita

Masayo Iwasa

Sayaka Kato

Hajime Yamakage

Takayoshi Suganami

Masashi Tanaka

Noriko Satoh-Asahara

Affiliations

Soon will be listed here.

Abstract

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1β) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.

Citing Articles

Gut-Brain Axis: Focus on Sex Differences in Neuroinflammation.

Caldarelli M, Rio P, Marrone A, Ocarino F, Chiantore M, Candelli M Int J Mol Sci. 2024; 25(10).

PMID: 38791415 PMC: 11120930. DOI: 10.3390/ijms25105377.

References

Li Y, Long W, Gao M, Jiao F, Chen Z, Liu M . TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway. Brain Sci. 2021; 11(7). PMC: 8306970. DOI: 10.3390/brainsci11070896. View

Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T . Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011; 77(12):1126-34. DOI: 10.1212/WNL.0b013e31822f0435. View

Wu J, Yang Y, Liu L, Zhu W, Liu M, Yu X . ROS-AMPK/mTOR-dependent enterocyte autophagy is involved in the regulation of infection-related tight junction protein and nitric oxide levels. Front Immunol. 2023; 14:1120996. PMC: 10043474. DOI: 10.3389/fimmu.2023.1120996. View

Plaza-Zabala A, Sierra-Torre V, Sierra A . Assessing Autophagy in Microglia: A Two-Step Model to Determine Autophagosome Formation, Degradation, and Net Turnover. Front Immunol. 2021; 11:620602. PMC: 7878397. DOI: 10.3389/fimmu.2020.620602. View

Detaille D, Vial G, Borel A, Cottet-Rouselle C, Hallakou-Bozec S, Bolze S . Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov. 2016; 2:15072. PMC: 4979505. DOI: 10.1038/cddiscovery.2015.72. View

Jo E, Kim J, Shin D, Sasakawa C . Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2015; 13(2):148-59. PMC: 4786634. DOI: 10.1038/cmi.2015.95. View

Ide M, Sonoda N, Inoue T, Kimura S, Minami Y, Makimura H . The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation. PLoS One. 2020; 15(2):e0228750. PMC: 7006898. DOI: 10.1371/journal.pone.0228750. View

Zhang J, Li L, Xiu F . Sesamin suppresses high glucose-induced microglial inflammation in the retina in vitro and in vivo. J Neurophysiol. 2022; 127(2):405-411. DOI: 10.1152/jn.00466.2021. View

Kato H, Minamizato H, Ohno H, Ohira Y, Izawa T . Exercise ameliorates high-fat diet-induced impairment of differentiation of adipose-derived stem cells into neuron-like cells in rats. J Cell Physiol. 2018; 234(2):1452-1460. DOI: 10.1002/jcp.26957. View

10.

Chong-Shan Shi , Shenderov K, Huang N, Kabat J, Abu-Asab M, Fitzgerald K . Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012; 13(3):255-63. PMC: 4116819. DOI: 10.1038/ni.2215. View

11.

Vial G, Chauvin M, Bendridi N, Durand A, Meugnier E, Madec A . Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes. 2015; 64(6):2254-64. DOI: 10.2337/db14-1220. View

12.

Ali M, Pearson-Stuttard J, Selvin E, Gregg E . Interpreting global trends in type 2 diabetes complications and mortality. Diabetologia. 2021; 65(1):3-13. PMC: 8660730. DOI: 10.1007/s00125-021-05585-2. View

13.

Maher P . Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells. Antioxidants (Basel). 2021; 10(1). PMC: 7828726. DOI: 10.3390/antiox10010109. View

14.

Fan X, Tian C, Wang H, Xu Y, Ren K, Zhang B . Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection. Sci Rep. 2015; 5:14728. PMC: 4589734. DOI: 10.1038/srep14728. View

15.

Heneka M, Golenbock D, Latz E . Innate immunity in Alzheimer's disease. Nat Immunol. 2015; 16(3):229-36. DOI: 10.1038/ni.3102. View

16.

Quan Y, Jiang C, Xue B, Zhu S, Wang X . High glucose stimulates TNFα and MCP-1 expression in rat microglia via ROS and NF-κB pathways. Acta Pharmacol Sin. 2011; 32(2):188-93. PMC: 4009937. DOI: 10.1038/aps.2010.174. View

17.

Heppner F, Ransohoff R, Becher B . Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015; 16(6):358-72. DOI: 10.1038/nrn3880. View

18.

Huang L, You J, Yao Y, Xie M . High glucose induces pyroptosis of retinal microglia through NLPR3 inflammasome signaling. Arq Bras Oftalmol. 2021; 84(1):67-73. DOI: 10.5935/0004-2749.20210010. View

19.

Papachristoforou E, Lambadiari V, Maratou E, Makrilakis K . Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications. J Diabetes Res. 2020; 2020:7489795. PMC: 7585656. DOI: 10.1155/2020/7489795. View

20.

Zhou X, Chen X, Cheng X, Lin L, Quan S, Li S . Paeoniflorin, ferulic acid, and atractylenolide III improved LPS-induced neuroinflammation of BV2 microglia cells by enhancing autophagy. J Pharmacol Sci. 2023; 152(2):151-161. DOI: 10.1016/j.jphs.2023.04.007. View