The Emerging Role of Mesenchymal Stem Cell-derived Extracellular Vesicles to Ameliorate Hippocampal NLRP3 Inflammation Induced by Binge-like Ethanol Treatment in Adolescence

Overview

Journal Neural Regen Res

Date 2024 Jul 11

PMID 38989953

Authors

Susana Mellado

Maria Jose Morillo-Bargues

Carla Perpina-Clerigues

Francisco Garcia-Garcia

Victoria Moreno-Manzano

Consuelo Guerri

Maria Pascual

Affiliations

Soon will be listed here.

Abstract

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

References

Ibanez F, Montesinos J, Urena-Peralta J, Guerri C, Pascual M . TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles. J Neuroinflammation. 2019; 16(1):136. PMC: 6610989. DOI: 10.1186/s12974-019-1529-x. View

Mira R, Lira M, Tapia-Rojas C, Rebolledo D, Quintanilla R, Cerpa W . Effect of Alcohol on Hippocampal-Dependent Plasticity and Behavior: Role of Glutamatergic Synaptic Transmission. Front Behav Neurosci. 2020; 13:288. PMC: 6993074. DOI: 10.3389/fnbeh.2019.00288. View

Mellado S, Cuesta C, Montagud S, Rodriguez-Arias M, Moreno-Manzano V, Guerri C . Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge-like ethanol treatment in adolescent mice. CNS Neurosci Ther. 2023; 29(12):4018-4031. PMC: 10651955. DOI: 10.1111/cns.14326. View

Quigley J . Alcohol Use by Youth. Pediatrics. 2019; 144(1). DOI: 10.1542/peds.2019-1356. View

Noori L, Arabzadeh S, Mohamadi Y, Mojaverrostami S, Mokhtari T, Akbari M . Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats. Neurosci Res. 2020; 170:87-98. DOI: 10.1016/j.neures.2020.07.011. View

Pascual M, Lopez-Hidalgo R, Montagud-Romero S, Urena-Peralta J, Rodriguez-Arias M, Guerri C . Role of mTOR-regulated autophagy in spine pruning defects and memory impairments induced by binge-like ethanol treatment in adolescent mice. Brain Pathol. 2020; 31(1):174-188. PMC: 8018167. DOI: 10.1111/bpa.12896. View

Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R . The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2022; 51(D1):D638-D646. PMC: 9825434. DOI: 10.1093/nar/gkac1000. View

Ibanez F, Urena-Peralta J, Costa-Alba P, Torres J, Laso F, Marcos M . Circulating MicroRNAs in Extracellular Vesicles as Potential Biomarkers of Alcohol-Induced Neuroinflammation in Adolescence: Gender Differences. Int J Mol Sci. 2020; 21(18). PMC: 7555060. DOI: 10.3390/ijms21186730. View

Jaszczyk A, Stankiewicz A, Juszczak G . Dissection of Mouse Hippocampus with Its Dorsal, Intermediate and Ventral Subdivisions Combined with Molecular Validation. Brain Sci. 2022; 12(6). PMC: 9221087. DOI: 10.3390/brainsci12060799. View

10.

Alfonso-Loeches S, Urena-Peralta J, Morillo-Bargues M, Oliver-De La Cruz J, Guerri C . Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci. 2014; 8:216. PMC: 4118026. DOI: 10.3389/fncel.2014.00216. View

11.

Wang L, Hauenstein A . The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med. 2020; 76:100889. DOI: 10.1016/j.mam.2020.100889. View

12.

Yin K, Wang S, Zhao R . Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark Res. 2019; 7:8. PMC: 6450000. DOI: 10.1186/s40364-019-0159-x. View

13.

Harrell C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V . Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells. 2019; 8(12). PMC: 6952783. DOI: 10.3390/cells8121605. View

14.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

15.

Hou B, Zhang Y, Liang P, He Y, Peng B, Liu W . Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype. Cell Death Dis. 2020; 11(5):377. PMC: 7229224. DOI: 10.1038/s41419-020-2565-2. View

16.

Glushakova O, Glushakov A, Wijesinghe D, Valadka A, Hayes R, Glushakov A . Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration. Brain Circ. 2018; 3(2):87-108. PMC: 6126261. DOI: 10.4103/bc.bc_27_16. View

17.

Jin X, Liu M, Zhang D, Zhong X, Du K, Qian P . Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF-κB signaling pathway. CNS Neurosci Ther. 2019; 25(5):575-590. PMC: 6488900. DOI: 10.1111/cns.13086. View

18.

Brust V, Schindler P, Lewejohann L . Lifetime development of behavioural phenotype in the house mouse (Mus musculus). Front Zool. 2016; 12 Suppl 1:S17. PMC: 4722345. DOI: 10.1186/1742-9994-12-S1-S17. View

19.

Vaka R, Parent S, Risha Y, Khan S, Courtman D, Stewart D . Extracellular vesicle microRNA and protein cargo profiling in three clinical-grade stem cell products reveals key functional pathways. Mol Ther Nucleic Acids. 2023; 32:80-93. PMC: 10034570. DOI: 10.1016/j.omtn.2023.03.001. View

20.

Ergin K, Cetinkaya R . Regulation of MicroRNAs. Methods Mol Biol. 2021; 2257:1-32. DOI: 10.1007/978-1-0716-1170-8_1. View