Regulation of the long noncoding RNA XIST on the inflammatory polarization of microglia in cerebral infarction

Zhang,Min; Yang,Jian-Kai; Ma,Jing

doi:10.3892/etm.2021.10356

Regulation of the long noncoding RNA XIST on the inflammatory polarization of microglia in cerebral infarction

Authors:
- Min Zhang
- Jian-Kai Yang
- Jing Ma
View Affiliations

Affiliations: Department of Neurosurgery, The Second Affiliated Hospital of Xingtai Medical College, Xingtai, Hebei 054000, P.R. China, Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Meteorological Service and Applied Meteorology, Ren County Meteorological Bureau of Hebei Province, Xingtai, Hebei 055150, P.R. China
Published online on: June 30, 2021 https://doi.org/10.3892/etm.2021.10356
Article Number: 924
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Proinflammatory polarization of microglia aggravates brain injury in cerebral infarction. The present study focused on the role of long non‑coding (lnc)RNA X‑inactive specific transcript (XIST) in the phenotype modulation of microglia. It was revealed that lncRNA XIST was significantly upregulated in both a mouse cerebral infarction model induced by middle cerebral artery occlusion (MCAO) and an activated microglial model induced by oxygen/glucose deprivation (OGD). The overexpression of XIST enhanced the expression and release of pro‑inflammatory mediators [such as tumor necrosis factor (TNF)‑α, IL‑6, and iNOS] in microglia. Culture supernatant from lncRNA XIST‑overexpressed microglial cells induced the apoptosis of primary neurons, while TNF‑α antibody counteracted this neurotoxic effect. LncRNA XIST served as a sponge for miR‑96‑5p, counteracting its inhibitory effect on IKKβ/NF‑κB signaling and TNF‑α production. Notably, TNF‑α was positively regulated by XIST and in turn enhanced XIST expression in microglia. The lncRNA XIST‑TNF‑α feedback promoted the proinflammatory polarization of microglia, thereby exacerbating cerebral neuron apoptosis.

View Figures

View References

1	Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 380:2095–2128. 2012.PubMed/NCBI View Article : Google Scholar
2	Wang C, Li N, Wang H, Yin H and Zhao Y: Study on essential drug use status and its influencing factors among cerebral infarction inpatients in county level hospitals of Anhui Province, China. PLoS One. 13(e0193513)2018.PubMed/NCBI View Article : Google Scholar
3	Holliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC, Cheng YC, Cotlarciuc I, Bis JC, Boerwinkle E, et al: Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke. 46:615–619. 2015.PubMed/NCBI View Article : Google Scholar
4	Puthanveetil P, Chen S, Feng B, Gautam A and Chakrabarti S: Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med. 19:1418–1425. 2015.PubMed/NCBI View Article : Google Scholar
5	Benakis C, Garcia-Bonilla L, Iadecola C and Anrather J: The role of microglia and myeloid immune cells in acute cerebral ischemia. Front Cell Neurosci. 8(461)2015.PubMed/NCBI View Article : Google Scholar
6	Seifert HA and Pennypacker KR: Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res. 5:543–553. 2014.PubMed/NCBI View Article : Google Scholar
7	Faustino JV, Wang X, Johnson CE, Klibanov A, Derugin N, Wendland MF and Vexler ZS: Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci. 31:12992–13001. 2011.PubMed/NCBI View Article : Google Scholar
8	Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y and Chen J: Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 43:3063–3070. 2012.PubMed/NCBI View Article : Google Scholar
9	Orihuela R, McPherson CA and Harry GJ: Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 173:649–665. 2016.PubMed/NCBI View Article : Google Scholar
10	Tang Y and Le W: Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 53:1181–1194. 2016.PubMed/NCBI View Article : Google Scholar
11	Bao MH, Szeto V, Yang BB, Zhu SZ, Sun HS and Feng ZP: Long non-coding RNAs in ischemic stroke. Cell Death Dis. 9(281)2018.PubMed/NCBI View Article : Google Scholar
12	Ren W and Yang X: Pathophysiology of long non-coding RNAs in ischemic stroke. Front Mol Neurosci. 11(96)2018.PubMed/NCBI View Article : Google Scholar
13	Dykstra-Aiello C, Jickling GC, Ander BP, Shroff N, Zhan X, Liu D, Hull H, Orantia M, Stamova BS and Sharp FR: Altered expression of long noncoding RNAs in blood after ischemic stroke and proximity to putative stroke risk loci. Stroke. 47:2896–2903. 2016.PubMed/NCBI View Article : Google Scholar
14	Yan H, Rao J, Yuan J, Gao L, Huang W, Zhao L and Ren J: Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell Death Dis. 8(3211)2017.PubMed/NCBI View Article : Google Scholar
15	Wang J, Zhao H, Fan Z, Li G, Ma Q, Tao Z, Wang R, Feng J and Luo Y: Long noncoding RNA H19 promotes neuroinflammation in ischemic stroke by driving histone deacetylase 1-dependent M1 microglial polarization. Stroke. 48:2211–2221. 2017.PubMed/NCBI View Article : Google Scholar
16	Gu S, Xie R, Liu X, Shou J, Gu W and Che X: Long coding RNA XIST contributes to neuronal apoptosis through the downregulation of AKT phosphorylation and is negatively regulated by miR-494 in rat spinal cord injury. Int J Mol Sci. 18(732)2017.PubMed/NCBI View Article : Google Scholar
17	Xu LX, Lv Y, Li YH, Ding X, Wang Y, Han X, Liu MH, Sun B and Feng X: Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: The involvement of edema related proteins. BMC Pediatr. 17(90)2017.PubMed/NCBI View Article : Google Scholar
18	Blanco S, Hernández R, Franchelli G, Ramos-Álvarez MM and Peinado MÁ: Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage. Nitric Oxide. 62:32–43. 2017.PubMed/NCBI View Article : Google Scholar
19	Ni J, Wang X, Chen S, Liu H, Wang Y, Xu X, Cheng J, Jia J and Zhen X: MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav Immun. 49:75–85. 2015.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Ridder DA and Schwaninger M: NF-kappaB signaling in cerebral ischemia. Neuroscience. 158:995–1006. 2009.PubMed/NCBI View Article : Google Scholar
22	Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Köhrmann M, Potrovita I, Maegele I, et al: IKK mediates ischemia-induced neuronal death. Nat Med. 11:1322–1319. 2005.PubMed/NCBI View Article : Google Scholar
23	Zhang YL, Li XB, Hou YX, Fang NZ, You JC and Zhou QH: The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer. Acta Pharmacol Sin. 38:371–381. 2017.PubMed/NCBI View Article : Google Scholar
24	Yao Y, Ma J, Xue Y, Wang P, Li Z, Liu J, Chen L, Xi Z, Teng H, Wang Z, et al: Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. Cancer Lett. 359:75–86. 2015.PubMed/NCBI View Article : Google Scholar
25	Jin H, Du XJ, Zhao Y and Xia DL: XIST/miR-544 axis induces neuropathic pain by activating STAT3 in a rat model. J Cell Physiol. 233:5847–5855. 2018.PubMed/NCBI View Article : Google Scholar
26	Yan XT, Lu JM, Wang Y, Cheng XL, He XH, Zheng WZ, Chen H and Wang YL: XIST accelerates neuropathic pain progression through regulation of miR-150 and ZEB1 in CCI rat models. J Cell Physiol. 233:6098–6106. 2018.PubMed/NCBI View Article : Google Scholar
27	Wang X, Wang C, Geng C and Zhao K: LncRNA XIST knockdown attenuates Aβ_25-3₅-induced toxicity, oxidative stress, and apoptosis in primary cultured rat hippocampal neurons by targeting miR-132. Int J Clin Exp Pathol. 11:3915–3924. 2018.PubMed/NCBI
28	Li WX, Qi F, Liu JQ, Li GH, Dai SX, Zhang T, Cheng F, Liu D and Zheng SG: Different impairment of immune and inflammation functions in short and long-term after ischemic stroke. Am J Transl Res. 9:736–745. 2017.PubMed/NCBI
29	Zhao Q, Lu F, Su Q, Liu Z, Xia X, Yan Z, Zhou F and Qin R: Knockdown of long noncoding RNA XIST mitigates the apoptosis and inflammatory injury of microglia cells after spinal cord injury through miR-27a/Smurf1 axis. Neurosci Lett. 715(134649)2020.PubMed/NCBI View Article : Google Scholar
30	Huang Y, Zhu N, Chen T, Chen W, Kong J, Zheng W and Ruan J: Triptolide suppressed the microglia activation to improve spinal cord injury through miR-96/IKKβ/NF-κB pathway. Spine (Phila Pa 1976). 44:E707–E714. 2019.PubMed/NCBI View Article : Google Scholar
31	Shi Y, Zhao Y, Shao N, Ye R, Lin Y, Zhang N, Li W, Zhang Y and Wang S: Overexpression of microRNA-96-5p inhibits autophagy and apoptosis and enhances the proliferation, migration and invasiveness of human breast cancer cells. Oncol Lett. 13:4402–4412. 2017.PubMed/NCBI View Article : Google Scholar
32	Kinoshita C, Aoyama K, Matsumura N, Kikuchi-Utsumi K, Watabe M and Nakaki T: Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels. Nat Commun. 5(3823)2014.PubMed/NCBI View Article : Google Scholar
33	Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T and Schwaninger M: NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 5:554–559. 1999.PubMed/NCBI View Article : Google Scholar
34	Shih RH, Wang CY and Yang CM: NF-kappaB signaling pathways in neurological inflammation: A mini review. Front Mol Neurosci. 8(77)2015.PubMed/NCBI View Article : Google Scholar
35	Gao W, Gao J, Chen L, Ren Y and Ma J: Targeting XIST induced apoptosis of human osteosarcoma cells by activation of NF-kB/PUMA signal. Bioengineered. 10:261–270. 2019.PubMed/NCBI View Article : Google Scholar