AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Journal of Neurorestoratology Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Research | Open Access

Inhibition of P2X7R alleviates neuroinflammation and brain edema after traumatic brain injury by suppressing the NF-κB/NLRP3 inflammasome pathway

Bingyan Taoa,b,c,1, Jie Peid,1, Hao Lie, Guochao Yangf, Xudong Shia,c, Zehan Zhangg, Hui Wangh, Zhou Zhengi, Yuyang Liuc,j,k( ), Jun Zhanga( )
Department of Neurosurgery, the First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China
Department of Neurosurgery, 961th Hospital of Joint Logistics Support Force, Qiqihar 161000, Heilongjiang, China
Medical School of Chinese PLA, Beijing 100853, China
Institute of Military Cognition and Brain Sciences, Beijing, 100850, China
Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China
Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210061, Jiangsu, China
Department of Neurosurgery, PLA Air Force Hospital of Southern Theatre Command, Guangzhou,510602, Guangdong, China
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China
Department of Emergency, 920th Hospital of Joint Logistics Support Force, Kunming 650032, Yunnan, China
Department of Neurosurgery, 920th Hospital of Joint Logistics Support Force, Kunming 650032, Yunnan, China
Chinese PLA Spinal Cord Injury Treatment Center, Kunming 650032, Yunnan, China

1 These authors contributed equally to this work.

Show Author Information

Abstract

Background

Purinergic ligand-gated ion channel 7 receptor (P2X7R) is an ATP-gated cationic channel. It plays an important role in central nervous system diseases such as cerebral hemorrhage and Parkinson's disease, and is closely related to neuroinflammatory reactions associated with disease progression. In the present study, we evaluated the role of P2X7R in neuroinflammation and brain edema after traumatic brain injury (TBI). We also investigated the related mechanisms and potential therapeutic drugs.

Methods

In the in vivo experiments, C57BL/6 mice were randomly divided into four groups: Sham, TBI, TBI + A438079, or TBI + MCC950. The TBI model was constructed via controlled cortical impact, and mice then received saline, A438079, or MCC950 injections. Morphological damage to the brains of mice was observed by Nissl staining. Morphological and quantitative changes in microglia as well as P2X7R expression were observed via immunofluorescence. The water content of brain tissue was evaluated using the brain dry/wet weight ratio. In the in vitro experiments, lipopolysaccharides were used to stimulate murine microglial BV2 cells into an inflammatory activation state. The expression of P2X7R, interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, nuclear factor kappa-B (NF-κB), and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasomes in BV2 cells was analyzed using enzyme-linked immunosorbent assay and Western blot. Moreover, an indirect co-culture technique was used to evaluate the effects of the neuroinflammatory model of BV2 cells on tight junction protein expression in mouse brain microvascular endothelial bEnd.3 cells.

Results

Levels of P2X7R, IL-1β, IL-6, IL-12, TNF-α, NF-κB, and NLRP3 inflammasomes were significantly higher in the TBI group than in the Sham group. TBI also increased the brain edema degree and tight junction protein expression levels. By targeting P2X7R (with A438079) or NLRP3 (with MCC950), we were able to inhibit neuroinflammation and alleviate brain edema.

Conclusions

Targeting P2X7R may help to reduce neuroinflammation and brain edema secondary to acute TBI by inhibiting the NF-κB/NLRP3 inflammasome pathway. P2X7R may be an innovative therapeutic target in TBI.

Keywords

Traumatic brain injuryNeuroinflammationNF-κBNLRP3Brain edemaP2X7R

References

1

Jiang JY, Gao GY, Feng JF, et al. Traumatic brain injury in China. Lancet Neurol. 2019;18(3):286–295. https://doi.org/10.1016/s1474-4422(18)30469-1.
Crossref Google Scholar
2

Greer K, Basso EKG, Kelly C, et al. Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments. Sci Rep. 2020;10(1):15374. https://doi.org/10.1038/s41598-020-72380-1.
Crossref Google Scholar
3

Rana A, Singh S, Sharma R, et al. Traumatic brain injury altered normal brain signaling pathways: implications for novel therapeutics approaches. Curr Neuropharmacol. 2019;17(7):614–629. https://doi.org/10.2174/1570159X 16666180911121847.
Crossref Google Scholar
4

Sandsmark DK, Bashir A, Wellington CL, et al. Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron. 2019;103(3):367–379. https://doi.org/10.1016/j.neuron.2019.06.002.
Crossref Google Scholar
5

Tan ZJ, Chen LL, Ren YC, et al. Neuroprotective effects of FK866 against traumatic brain injury: involvement of p38/ERK pathway. Ann Clin Transl Neurol. 2020;7(5):742–756. https://doi.org/10.1002/acn3.51044.
Crossref Google Scholar
6

Song YB, Cao CY, Xu QY, et al. Piperine attenuates TBI-induced seizures via inhibiting cytokine-activated reactive astrogliosis. Front Neurol. 2020;11:431. https://doi.org/10.3389/fneur.2020.00431.
Crossref Google Scholar
7

Yoon CS, Kim DC, Park JS, et al. Isolation of novel sesquiterpeniods and antineuroinflammatory metabolites from Nardostachys jatamansi. Molecules. 2018;23(9):2367. https://doi.org/10.3390/molecules23092367.
Crossref Google Scholar
8

Shah MA, Park DJ, Kang JB, et al. Baicalin alleviates lipopolysaccharide-induced neuroglial activation and inflammatory factors activation in hippocampus of adult mice. Lab Anim Res. 2020;36:32. https://doi.org/10.1186/s42826-020-00058-w.
Crossref Google Scholar
9

Manzoor R, Rasool A, Ahmed M, et al. Synergistic neuroprotective effect of endogenously-produced hydroxytyrosol and synaptic vesicle proteins on pheochromocytoma cell line against salsolinol. Molecules. 2020;25(7):1715. https://doi.org/10.3390/molecules25071715.
Crossref Google Scholar
10

Zusman BE, Kochanek PM, Jha RM. Cerebral edema in traumatic brain injury: a historical framework for current therapy. Curr Treat Options Neurol. 2020;22(3):9. https://doi.org/10.1007/s11940-020-0614-x.
Crossref Google Scholar
11

Keep RF, Zhou NN, Xiang JM, et al. Vascular disruption and blood-brain barrier dysfunction in intracerebral hemorrhage. Fluids Barriers CNS. 2014;11:18. https://doi.org/10.1186/2045-8118-11-18.
Crossref Google Scholar
12

Behrens M, Hüwel S, Galla HJ, et al. Efflux at the blood-brain barrier reduces the cerebral exposure to ochratoxin A, ochratoxin a, citrinin and dihydrocitrinone. Toxins. 2021;13(5):327. https://doi.org/10.3390/toxins13050327.
Crossref Google Scholar
13

Li WL, Chen ZG, Chin I, et al. The role of VE-cadherin in blood-brain barrier integrity under central nervous system pathological conditions. Curr Neuropharmacol. 2018;16(9):1375–1384. https://doi.org/10.2174/1570159x166661 80222164809.
Crossref Google Scholar
14

Li WL, Chen ZG, Yuan J, et al. Annexin A2 is a Robo 4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability. J Cerebr Blood Flow Metabol. 2019;39(10):2048–2060. https://doi.org/10.1177/0271678x18777916.
Crossref Google Scholar
15

Bhattacharya A, Biber K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia. 2016;64(10):1772–1787. https://doi.org/10.1002/glia.23001.
Crossref Google Scholar
16

Qian YY, Qian C, Xie KW, et al. P2X7 receptor signaling promotes inflammation in renal parenchymal cells suffering from ischemia-reperfusion injury. Cell Death Dis. 2021;12(1):132. https://doi.org/10.1038/s41419-020-03384-y.
Crossref Google Scholar
17

Wang M, Deng XL, Xie YM, et al. Astaxanthin attenuates neuroinflammation in status epilepticus rats by regulating the ATP-P2X7R signal. Drug Des Dev Ther. 2020;14:1651–1662. https://doi.org/10.2147/dddt.S249162.
Crossref Google Scholar
18

Yue N, Huang HJ, Zhu XC, et al. Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stressinduced depressive-like behaviors. J Neuroinflammation. 2017;14(1):102. https://doi.org/10.1186/s12974-017-0865-y.
Crossref Google Scholar
19

Solini A, Rossi C, Santini E, et al. P2X7 receptor/NLRP3 inflammasome complex and a-synuclein in peripheral blood mononuclear cells: a prospective study in neo-diagnosed, treatment-naïve Parkinson's disease. Eur J Neurol. 2021;28(8):2648–2656. https://doi.org/10.1111/ene.14918.
Crossref Google Scholar
20

Chen YH, Lin RR, Tao QQ. The role of P2X7R in neuroinflammation and implications in Alzheimer's disease. Life Sci. 2021;271:119187. https://doi.org/10.1016/j.lfs.2021.119187.
Crossref Google Scholar
21

Jiang W, Li MQ, He F, et al. Targeting the NLRP3 inflammasome to attenuate spinal cord injury in mice. J Neuroinflammation. 2017;14(1):207. https://doi.org/10.1186/s12974-017-0980-9.
Crossref Google Scholar
22

Gao RF, Shi HR, Chang SC, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharm. 2019;74:105575. https://doi.org/10.1016/j.intimp.2019.04.022.
Crossref Google Scholar
23

Sawant-Pokam PA, Vail TJ, Metcalf CS, et al. Preventing neuronal edema increases network excitability after traumatic brain injury. J Clin Invest. 2020;130(11):6005–6020. https://doi.org/10.1172/jci134793.
Crossref Google Scholar
24

Ponten F, Jirström K, Uhlen M. The human protein atlas—a tool for pathology. J Pathol. 2008;216(4):387–393. https://doi.org/10.1002/path.2440.
Crossref Google Scholar
25

Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of useruploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–D612. https://doi.org/10.1093/nar/gkaa1074.
Crossref Google Scholar
26

Zhou YY, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. https://doi.org/10.1038/s41467-019-09234-6.
Crossref Google Scholar
27

Hopp S, Nolte MW, Stetter C, et al. Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa. J Neuroinflammation. 2017;14(1):39. https://doi.org/10.1186/s12974-017-0815-8.
Crossref Google Scholar
28

Wang HY, Huang QB, Zhang ZJ, et al. Transient post-operative overexpression of CXCR2 on monocytes of traumatic brain injury patients drives monocyte chemotaxis toward cerebrospinal fluid and enhances monocyte-mediated immunogenic cell death of neurons in vitro. J Neuroinflammation. 2022;19(1):171. https://doi.org/10.1186/s12974-022-02535-6.
Crossref Google Scholar
29

Jiang TF, Hoekstra J, Heng X, et al. P2X7 receptor is critical in a-synucleindmediated microglial NADPH oxidase activation. Neurobiol Aging. 2015;36(7):2304–2318. https://doi.org/10.1016/j.neurobiolaging.2015.03.015.
Crossref Google Scholar
30

Chai YH, Cai YW, Fu Y, et al. Salidroside ameliorates depression by suppressing NLRP3-mediated pyroptosis via P2X7/NF-κB/NLRP3 signaling pathway. Front Pharmacol. 2022;13:812362. https://doi.org/10.3389/fphar.2022.812362.
Crossref Google Scholar
31

Bolte AC, Lukens JR. Neuroimmune cleanup crews in brain injury. Trends Immunol. 2021;42(6):480–494. https://doi.org/10.1016/j.it.2021.04.003.
Crossref Google Scholar
32

Witcher KG, Bray CE, Chunchai T, et al. Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by microglia. J Neurosci. 2021;41(7):1597–1616. https://doi.org/10.1523/jneurosci.2469-20.2020.
Crossref Google Scholar
33

Clevenger AC, Kim H, Salcedo E, et al. Endogenous sex steroids dampen neuroinflammation and improve outcome of traumatic brain injury in mice. J Mol Neurosci. 2018;64(3):410–420. https://doi.org/10.1007/s12031-018-1038-x.
Crossref Google Scholar
34

Spellicy SE, Stice SL. Tissue and stem cell sourced extracellular vesicle communications with microglia. Stem Cell Rev Rep. 2021;17(2):357–368. https://doi.org/10.1007/s12015-020-10011-y.
Crossref Google Scholar
35

Liu XF, Zhao ZQ, Ji RH, et al. Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats. Purinergic Signal. 2017;13(4):529–544. https://doi.org/10.1007/s11302-017-9579-y.
Crossref Google Scholar
36

Zhao HL, Pan PY, Yang Y, et al. Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats. J Neuroinflammation. 2017;14(1):163. https://doi.org/10.1186/s12974-017-0940-4.
Crossref Google Scholar
37

Sperlagh B, Illes P. P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci. 2014;35(10):537–547. https://doi.org/10.1016/j.tips.2014.08.002.
Crossref Google Scholar
38

Stephenson J, Nutma E, van der Valk P, et al. Inflammation in CNS neurodegenerative diseases. Immunology. 2018;154(2):204–219. https://doi.org/10.1111/imm.12922.
Crossref Google Scholar
39

Orsini F, Fumagalli S, Császár E, et al. Mannose-binding lectin drives platelet inflammatory phenotype and vascular damage after cerebral ischemia in mice via IL (interleukin)-1α. Arterioscler Thromb Vasc Biol. 2018;38(11):2678–2690. https://doi.org/10.1161/atvbaha.118.311058.
Crossref Google Scholar
40

Kim S, Steelman AJ, Koito H, et al. Astrocytes promote TNF-mediated toxicity to oligodendrocyte precursors. J Neurochem. 2011;116(1):53–66. https://doi.org/10.1111/j.1471-4159.2010.07084.x.
Crossref Google Scholar
41

Wan YF, Holste KG, Hua Y, et al. Brain edema formation and therapy after intracerebral hemorrhage. Neurobiol Dis. 2023;176:105948. https://doi.org/10.1016/j.nbd.2022.105948.
Crossref Google Scholar
42

Sato K, Nakagawa S, Morofuji Y, et al. Effects of fasudil on blood-brain barrier integrity. Fluids Barriers CNS. 2022;19(1):43. https://doi.org/10.1186/s12987-022-00336-w.
Crossref Google Scholar
43

Feng L, Chen YZ, Ding R, et al. P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage:involvement of peroxynitrite. J Neuroinflammation. 2015;12:190. https://doi.org/10.1186/s12974-015-0409-2.
Crossref Google Scholar
44

Marcellino D, Suárez-Boomgaard D, Sánchez-Reina MD, et al. On the role of P2X(7) receptors in dopamine nerve cell degeneration in a rat model of Parkinson's disease: studies with the P2X(7) receptor antagonist A-438079. J Neural Transm. 2010;117(6):681–687. https://doi.org/10.1007/s00702-010-0400-0.
Crossref Google Scholar
45

Lee HG, Won SM, Gwag BJ, et al. Microglial P2X7 receptor expression is accompanied by neuronal damage in the cerebral cortex of the APPswe/PS1dE9 mouse model of Alzheimer's disease. Exp Mol Med. 2011;43(1):7–14. https://doi.org/10.3858/emm.2011.43.1.001.
Crossref Google Scholar
46

Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–489. https://doi.org/10.1038/s41577-019-0165-0.
Crossref Google Scholar
47

Hayward JA, Mathur A, Ngo C, et al. Cytosolic recognition of microbes and pathogens: inflammasomes in action. Microbiol Mol Biol Rev. 2018;82(4):e00015–e00018. https://doi.org/10.1128/mmbr.00015-18.
Crossref Google Scholar
48

Singh S, Jha S. NLRs as helpline in the brain: mechanisms and therapeutic implications. Mol Neurobiol. 2018;55(10):8154–8178. https://doi.org/10.1007/s12035-018-0957-4.
Crossref Google Scholar
49

Zou P, Liu XX, Li G, et al. Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. Mol Med Rep. 2018;17(2):3212–3217. https://doi.org/10.3892/mmr.2017.8241.
Crossref Google Scholar
50

Salla M, Butler MS, Pelingon R, et al. Identification, synthesis, and biological evaluation of the major human metabolite of NLRP3 inflammasome inhibitor MCC950. ACS Med Chem Lett. 2016;7(12):1034–1038. https://doi.org/10.1021/acsmedchemlett.6b00198.
Crossref Google Scholar
51

Coll RC, Robertson AAB, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–255. https://doi.org/10.1038/nm.3806.
Crossref Google Scholar
52

Ren HL, Kong Y, Liu ZJ, et al. Selective NLRP3 (pyrin domain-containing protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage. Stroke. 2018;49(1):184–192. https://doi.org/10.1161/strokeaha.117.018904.
Crossref Google Scholar
53

Dempsey C, Rubio Araiz A, Bryson KJ, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-b and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017;61:306–316. https://doi.org/10.1016/j.bbi.2016.12.014.
Crossref Google Scholar
54

Ke BL, Zhao ZY, Ye X, et al. Inactivation of NF-κB p65 (RelA) in liver improves insulin sensitivity and inhibits cAMP/PKA pathway. Diabetes. 2015;64(10):3355–3362. https://doi.org/10.2337/db15-0242.
Crossref Google Scholar
55

Liu X, Jia YL, Chong LM, et al. Effects of oral cimetidine on the reproductive system of male rats. Exp Ther Med. 2018;15(6):4643–4650. https://doi.org/10.3892/etm.2018.6065.
Crossref Google Scholar
56

Mettang M, Reichel SN, Lattke M, et al. IKK2/NF-κB signaling protects neurons after traumatic brain injury. Faseb J. 2018;32(4):1916–1932. https://doi.org/10.1096/fj.201700826R.
Crossref Google Scholar
57

Lu YJ, Liu X, Xie MH, et al. The NF-κB-responsive long noncoding RNA FIRRE regulates posttranscriptional regulation of inflammatory gene expression through interacting with hnRNPU. J Immunol. 2017;199(10):3571–3582. https://doi.org/10.4049/jimmunol.1700091.
Crossref Google Scholar
58

Zang YH, Zhou XY, Wang Q, et al. LncRNA FIRRE/NF-κB feedback loop contributes to OGD/R injury of cerebral microglial cells. Biochem Biophys Res Commun. 2018;501(1):131–138. https://doi.org/10.1016/j.bbrc.2018.04.194.
Crossref Google Scholar
59

Xu S, Chen HW, Ni HE, et al. Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-κB/NLRP3 pathway. Atherosclerosis. 2021;317:1–9. https://doi.org/10.1016/j.atherosclerosis.2020.11.021.
Crossref Google Scholar
60

Deng YF, Xu QQ, Chen TQ, et al. Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway. Phytomedicine. 2022;104:154241. https://doi.org/10.1016/j.phymed.2022.154241.
Crossref Google Scholar
61

Peng L, Wen L, Shi QF, et al. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. 2020;11(11):978. https://doi.org/10.1038/s41419-020-03178-2.
Crossref Google Scholar
Journal of Neurorestoratology
Volume 12 Issue 2,
June 2024
Article number: 100106
DOI: 10.1016/j.jnrt.2024.100106
Cite this article:
Tao B, Pei J, Li H, et al. Inhibition of P2X7R alleviates neuroinflammation and brain edema after traumatic brain injury by suppressing the NF-κB/NLRP3 inflammasome pathway. Journal of Neurorestoratology, 2024, 12(2): 100106. https://doi.org/10.1016/j.jnrt.2024.100106

163

Views

0

Crossref

0

Web of Science

0

Scopus

Altmetrics
Received: 21 November 2023
Revised: 07 January 2024
Accepted: 18 January 2024
Published: 29 February 2024
© 2024

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Return