MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting EEF1A1

Overview

Journal Front Pharmacol

Date 2021 Sep 24

PMID 34557098

Citations 8

Authors

Yulan Liu

Shanshan Deng

Zhibing Song

Qian Zhang

Yuchen Guo

Yongsheng Yu

Yuliang Wang

Tiejun Li

Fayed A K Megahed

Tamer A Addissouky

Junqin Mao

Yuefan Zhang

Affiliations

Soon will be listed here.

Abstract

Monocyte locomotion inhibitory factor (MLIF) is a heat-stable pentapeptide from . Our previous study found that MLIF protects against ischemic stroke in rats and mice and exerts a neuroprotection effect in human neuroblastoma SH-SY5Y cells. Microglia/macrophage polarization has been proven to be vital in the pathology of ischemic stroke. Nevertheless, whether MLIF is able to modulate microglia/macrophage polarization remains unclear. We performed middle cerebral artery occlusion (MCAO) on C57BL/6J male mice and induced cultured BV2 microglia by oxygen-glucose deprivation (OGD), respectively. Immunfluorescence was utilized to detect the M1/2 markers, such as CD206 and CD16/32. qPCR and ELISA were used to detect the signature gene change of M1/2. The MAPK and NF-κB pathway associated proteins were measured by Western blot. To identify the protein target of MLIF, a pull-down assay was performed. We found that MLIF promoted microglia transferring from a "sick" M1 phenotype to a "healthy" M2 phenotype or . Furthermore, we proved that eukaryotic elongation factor 1A1 (eEF1A1) was involved in the modulation of microglia/macrophage polarization. Knocking down eEF1A1 by siRNA exhibited the M1 promotion effect and M2 inhibition effect. Taken together, our results demonstrated MLIF modulated microglia/macrophage polarization by targeting eEF1A1 in ischemic stroke.

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References

Liu S, Hausmann S, Carlson S, Fuentes M, Francis J, Pillai R . METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis. Cell. 2019; 176(3):491-504.e21. PMC: 6499081. DOI: 10.1016/j.cell.2018.11.038. View

Akintade D, Chaudhuri B . Identification of proteins involved in transcription/translation (eEF 1A1) as an inhibitor of Bax induced apoptosis. Mol Biol Rep. 2020; 47(9):6785-6792. PMC: 7561549. DOI: 10.1007/s11033-020-05736-5. View

Abbas W, Kumar A, Herbein G . The eEF1A Proteins: At the Crossroads of Oncogenesis, Apoptosis, and Viral Infections. Front Oncol. 2015; 5:75. PMC: 4387925. DOI: 10.3389/fonc.2015.00075. View

Han D, Wang J, Wen L, Sun M, Liu H, Gao Y . Remote Limb Ischemic Postconditioning Protects against Ischemic Stroke via Modulating Microglia/Macrophage Polarization in Mice. J Immunol Res. 2021; 2021:6688053. PMC: 7910075. DOI: 10.1155/2021/6688053. View

Barthels D, Das H . Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis. 2019; 1866(4):165260. PMC: 6981280. DOI: 10.1016/j.bbadis.2018.09.012. View

Lian L, Zhang Y, Liu L, Yang L, Cai Y, Zhang J . Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia. Front Mol Neurosci. 2021; 13:612439. PMC: 7817943. DOI: 10.3389/fnmol.2020.612439. View

Jiang C, Wu W, Deng Y, Ge J . Modulators of microglia activation and polarization in ischemic stroke (Review). Mol Med Rep. 2020; 21(5):2006-2018. PMC: 7115206. DOI: 10.3892/mmr.2020.11003. View

Kwon H, Koh S . Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020; 9(1):42. PMC: 7689983. DOI: 10.1186/s40035-020-00221-2. View

Duman M, Vaquie A, Nocera G, Heller M, Stumpe M, Sankar D . EEF1A1 deacetylation enables transcriptional activation of remyelination. Nat Commun. 2020; 11(1):3420. PMC: 7347577. DOI: 10.1038/s41467-020-17243-z. View

10.

Knight J, Garland G, Poyry T, Mead E, Vlahov N, Sfakianos A . Control of translation elongation in health and disease. Dis Model Mech. 2020; 13(3). PMC: 7104864. DOI: 10.1242/dmm.043208. View

11.

Jayaraj R, Azimullah S, Beiram R, Jalal F, Rosenberg G . Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019; 16(1):142. PMC: 6617684. DOI: 10.1186/s12974-019-1516-2. View

12.

Qian M, Wang S, Guo X, Wang J, Zhang Z, Qiu W . Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways. Oncogene. 2019; 39(2):428-442. DOI: 10.1038/s41388-019-0996-y. View

13.

Li D, Rawle D, Wu Z, Jin H, Lin M, Lor M . eEF1A demonstrates paralog specific effects on HIV-1 reverse transcription efficiency. Virology. 2019; 530:65-74. DOI: 10.1016/j.virol.2019.01.023. View

14.

Jimi E, Fei H, Nakatomi C . NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis. Int J Mol Sci. 2019; 20(24). PMC: 6941088. DOI: 10.3390/ijms20246275. View

15.

Hu X, Leak R, Shi Y, Suenaga J, Gao Y, Zheng P . Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol. 2014; 11(1):56-64. PMC: 4395497. DOI: 10.1038/nrneurol.2014.207. View

16.

Yao J, Xu Y, Ji F, Wang C, Zhang Y, Ni J . Protective effects of MLIF analogs on cerebral ischemia-reperfusion injury in rats. Peptides. 2011; 32(5):1047-54. DOI: 10.1016/j.peptides.2011.03.005. View

17.

Wei S, Wang D, Li H, Bi L, Deng J, Zhu G . Fatty acylCoA synthetase FadD13 regulates proinflammatory cytokine secretion dependent on the NF-κB signalling pathway by binding to eEF1A1. Cell Microbiol. 2019; 21(12):e13090. PMC: 6899955. DOI: 10.1111/cmi.13090. View

18.

Zhang G, Xia F, Zhang Y, Zhang X, Cao Y, Wang L . Ginsenoside Rd Is Efficacious Against Acute Ischemic Stroke by Suppressing Microglial Proteasome-Mediated Inflammation. Mol Neurobiol. 2015; 53(4):2529-40. DOI: 10.1007/s12035-015-9261-8. View

19.

Greenhalgh A, David S, Bennett F . Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci. 2020; 21(3):139-152. DOI: 10.1038/s41583-020-0263-9. View

20.

White K, Rosales R, Yildiz S, Kehrer T, Miorin L, Moreno E . Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 2021; 371(6532):926-931. PMC: 7963220. DOI: 10.1126/science.abf4058. View