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Cited by 109Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson’s disease via the microglial NLRP3 inflammasome

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Kou, Liang, Chi, Xiaosa, Sun, Yadi, Han, Chao, Wan, Fang, Hu, Junjie, Yin, Sijia, Wu, Jiawei +7 more·2022·Journal of Neuroinflammation
DOI 10.1186/s12974-022-02494-yPMC PMC9169406
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Abstract

BACKGROUND: Circadian disturbance is a common nonmotor complaint in Parkinson's disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis. METHODS: ) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail. RESULTS: BV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system. CONCLUSIONS: These observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.

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  • BMAL1 may affect glial cell activation and neurodegeneration through REV-ERBα.

    “Further studies suggested that BMAL1 may affect glial cells activation and neurodegeneration through REV-ERBα, which is a nuclear receptor as well as a circadian clock component that can be induced by BMAL1.123–125”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [124]

    The Introduction (page unavailable) reports that loss of either BMAL1 or REV-ERBα is associated with microglial activation, and that REV-ERBα deficiency exacerbates dopaminergic neurodegeneration. The Discussion (page unavailable) also reports that REV-ERBα activation attenuates microglial activation. But the paper does not establish that BMAL1 affects these outcomes through REV-ERBα, or state that BMAL1 induces REV-ERBα. (LLM, conf=0.83)

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References 55 · Cited by 109

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  1. [1]Barone P Antonini A Colosimo C The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease Mov Disord 2009 24 11 1641 1649 10.1002/mds.22643 19514014 · DOI · Paper page
  2. [2]Videnovic A Lazar AS Barker RA Overeem S 'The clocks that time us'—circadian rhythms in neurodegenerative disorders Nat Rev Neurol 2014 10 12 683 693 10.1038/nrneurol.2014.206 25385339 PMC4344830 · DOI
  3. [3]Christopher L Koshimori Y Lang AE Criaud M Strafella AP Uncovering the role of the insula in non-motor symptoms of Parkinson's disease Brain 2014 137 Pt 8 2143 2154 10.1093/brain/awu084 24736308 PMC4107733 · DOI
  4. [4]Leng Y Blackwell T Cawthon PM Ancoli-Israel S Stone KL Yaffe K Association of circadian abnormalities in older adults with an increased risk of developing Parkinson disease JAMA Neurol 2020 77 10 1270 1278 10.1001/jamaneurol.2020.1623 32539075 PMC7296450 · DOI
  5. [5]Leng Y Musiek ES Hu K Cappuccio FP Yaffe K Association between circadian rhythms and neurodegenerative diseases Lancet Neurol 2019 18 3 307 318 10.1016/S1474-4422(18)30461-7 30784558 PMC6426656 · DOI
  6. [7]Lauretti E Di Meco A Merali S Pratico D Circadian rhythm dysfunction: a novel environmental risk factor for Parkinson’s disease Mol Psychiatry 2017 22 2 280 286 10.1038/mp.2016.47 27046648 · DOI
  7. [8]Liu WW Wei SZ Huang GD BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model FASEB J 2020 34 5 6570 6581 10.1096/fj.201901565RR 32246801 · DOI
  8. [9]Stephenson J Nutma E van der Valk P Amor S Inflammation in CNS neurodegenerative diseases Immunology 2018 154 2 204 219 10.1111/imm.12922 29513402 PMC5980185 · DOI · Paper page
  9. [11]Gordon R Albornoz EA Christie DC Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice Sci Transl Med 2018 10 465 eaah4066 10.1126/scitranslmed.aah4066 30381407 PMC6483075 · DOI · Paper page
  10. [12]Han X Sun S Sun Y Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease Autophagy 2019 15 11 1860 1881 10.1080/15548627.2019.1596481 30966861 PMC6844502 · DOI · Paper page
  11. [13]Yan S Wei X Jian W Pharmacological inhibition of HDAC6 attenuates NLRP3 inflammatory response and protects dopaminergic neurons in experimental models of Parkinson's disease Front Aging Neurosci 2020 12 78 10.3389/fnagi.2020.00078 32296327 PMC7137996 · DOI
  12. [14]Trudler D Nazor KL Eisele YS Soluble alpha-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia Proc Natl Acad Sci USA 2021 118 15 e2025847118 10.1073/pnas.2025847118 33833060 PMC8054017 · DOI
  13. [15]von Herrmann KM Salas LA Martinez EM NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson's disease NPJ Parkinsons Dis 2018 4 24 10.1038/s41531-018-0061-5 30131971 PMC6093937 · DOI
  14. [16]Li Q Wang Z Xing H Wang Y Guo Y Exosomes derived from miR-188-3p-modified adipose-derived mesenchymal stem cells protect Parkinson's disease Mol Ther Nucleic Acids 2021 23 1334 1344 10.1016/j.omtn.2021.01.022 33717653 PMC7920810 · DOI
  15. [19]Lananna BV Nadarajah CJ Izumo M Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1 Cell Rep 2018 25 1 1 9.e5 10.1016/j.celrep.2018.09.015 30282019 PMC6221830 · DOI
  16. [20]Griffin P Sheehan PW Dimitry JM REV-ERBalpha mediates complement expression and diurnal regulation of microglial synaptic phagocytosis Elife 2020 9 e58765 10.7554/eLife.58765 33258449 PMC7728439 · DOI · Paper page
  17. [21]Ni J Wu Z Meng J An impaired intrinsic microglial clock system induces neuroinflammatory alterations in the early stage of amyloid precursor protein knock-in mouse brain J Neuroinflamm 2019 16 1 173 10.1186/s12974-019-1562-9 PMC6716829 31470863 · DOI
  18. [22]Griffin P Dimitry JM Sheehan PW Circadian clock protein Rev-erbalpha regulates neuroinflammation Proc Natl Acad Sci USA 2019 116 11 5102 5107 10.1073/pnas.1812405116 30792350 PMC6421453 · DOI · Paper page
  19. [23]Guo DK Zhu Y Sun HY Pharmacological activation of REV-ERBalpha represses LPS-induced microglial activation through the NF-kappaB pathway Acta Pharmacol Sin 2019 40 1 26 34 10.1038/s41401-018-0064-0 29950615 PMC6318300 · DOI
  20. [24]Kim J Jang S Choi M Abrogation of the circadian nuclear receptor REV-ERBalpha exacerbates 6-hydroxydopamine-induced dopaminergic neurodegeneration Mol Cells 2018 41 8 742 752 30078232 PMC6125424
  21. [25]Yan M Xiong M Dai L Cofilin 1 promotes the pathogenicity and transmission of pathological alpha-synuclein in mouse models of Parkinson's disease NPJ Parkinsons Dis 2022 8 1 1 10.1038/s41531-021-00272-w 35013321 PMC8748615 · DOI
  22. [26]Xia Y Zhang G Han C Microglia as modulators of exosomal alpha-synuclein transmission Cell Death Dis 2019 10 3 174 10.1038/s41419-019-1404-9 30787269 PMC6382842 · DOI
  23. [27]Harms AS Ferreira SA Romero-Ramos M Periphery and brain, innate and adaptive immunity in Parkinson's disease Acta Neuropathol 2021 141 4 527 545 10.1007/s00401-021-02268-5 33555429 PMC7952334 · DOI
  24. [28]Andersen MS Bandres-Ciga S Reynolds RH Heritability enrichment implicates microglia in Parkinson's disease pathogenesis Ann Neurol 2021 89 5 942 951 10.1002/ana.26032 33502028 PMC9017316 · DOI
  25. [29]Kwon HS Koh SH Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes Transl Neurodegener 2020 9 1 42 10.1186/s40035-020-00221-2 33239064 PMC7689983 · DOI · Paper page
  26. [30]Lee E Hwang I Park S MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration Cell Death Differ 2019 26 2 213 228 10.1038/s41418-018-0124-5 29786072 PMC6329843 · DOI · Paper page
  27. [31]Musiek ES Holtzman DM Mechanisms linking circadian clocks, sleep, and neurodegeneration Science 2016 354 6315 1004 1008 10.1126/science.aah4968 27885006 PMC5219881 · DOI · Paper page
  28. [32]Fifel K Alterations of the circadian system in Parkinson's disease patients Mov Disord 2017 32 5 682 692 10.1002/mds.26865 27859638 · DOI
  29. [33]Xia Y Kou L Zhang G Investigation on sleep and mental health of patients with Parkinson's disease during the Coronavirus disease 2019 pandemic Sleep Med 2020 75 428 433 10.1016/j.sleep.2020.09.011 32980664 PMC7481072 · DOI
  30. [34]Preitner N Damiola F Lopez-Molina L The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator Cell. 2002 110 2 251 260 10.1016/S0092-8674(02)00825-5 12150932 · DOI · Paper page
  31. [35]Crumbley C Burris TP Direct regulation of CLOCK expression by REV-ERB PLoS ONE 2011 6 3 e17290 10.1371/journal.pone.0017290 21479263 PMC3066191 · DOI
  32. [36]Cho H Zhao X Hatori M Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta Nature 2012 485 7396 123 127 10.1038/nature11048 22460952 PMC3367514 · DOI · Paper page
  33. [37]Shen W Zhang W Ye W SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy Theranostics 2020 10 10 4466 4480 10.7150/thno.42478 32292508 PMC7150483 · DOI
  34. [38]Sulli G Rommel A Wang X Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence Nature 2018 553 7688 351 355 10.1038/nature25170 29320480 PMC5924733 · DOI
  35. [39]Gibbs JE Blaikley J Beesley S The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines Proc Natl Acad Sci USA 2012 109 2 582 587 10.1073/pnas.1106750109 22184247 PMC3258648 · DOI
  36. [40]Lee J Kim DE Griffin P Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease Aging Cell 2019 19 2 e13078 31800167 PMC6996949
  37. [41]Yue J He J Wei Y Decreased expression of Rev-Erbalpha in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbalpha have anti-inflammatory and neuroprotective effects in the pilocarpine model J Neuroinflamm 2020 17 1 43 10.1186/s12974-020-1718-7 PMC6993411 32005256 · DOI
  38. [42]Madore C Yin Z Leibowitz J Butovsky O Microglia, lifestyle stress, and neurodegeneration Immunity 2020 52 2 222 240 10.1016/j.immuni.2019.12.003 31924476 PMC7234821 · DOI
  39. [43]Xia Y Zhang G Kou L Reactive microglia enhance the transmission of exosomal alpha-synuclein via toll-like receptor 2 Brain 2021 144 7 2024 2037 10.1093/brain/awab122 33792662 · DOI · Paper page
  40. [44]Shen Y Guo X Han C The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease Cell Mol Life Sci 2017 74 20 3741 3768 10.1007/s00018-017-2549-2 28623510 PMC11107509 · DOI
  41. [45]Heneka MT McManus RM Latz E Inflammasome signalling in brain function and neurodegenerative disease Nat Rev Neurosci 2018 19 10 610 621 10.1038/s41583-018-0055-7 30206330 · DOI · Paper page
  42. [46]Pandey A Shen C Feng S Man SM Cell biology of inflammasome activation Trends Cell Biol 2021 31 11 924 939 10.1016/j.tcb.2021.06.010 34284921 · DOI
  43. [47]Slusarczyk J Trojan E Glombik K Targeting the NLRP3 inflammasome-related pathways via tianeptine treatment-suppressed microglia polarization to the M1 phenotype in lipopolysaccharide-stimulated cultures Int J Mol Sci 2018 19 7 1965 10.3390/ijms19071965 PMC6073715 29976873 · DOI
  44. [48]Wang S Lin Y Yuan X Li F Guo L Wu B REV-ERBalpha integrates colon clock with experimental colitis through regulation of NF-kappaB/NLRP3 axis Nat Commun 2018 9 1 4246 10.1038/s41467-018-06568-5 30315268 PMC6185905 · DOI
  45. [49]Lei H Ren R Sun Y Neuroprotective effects of safflower flavonoid extract in 6-hydroxydopamine-induced model of Parkinson's disease may be related to its anti-inflammatory action Molecules 2020 25 21 5206 10.3390/molecules25215206 PMC7664856 33182332 · DOI
  46. [50]Zhang C Zhao M Wang B The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease Redox Biol 2021 47 102134 10.1016/j.redox.2021.102134 34600334 PMC8487081 · DOI
  47. [51]Panicker N Sarkar S Harischandra DS Fyn kinase regulates misfolded alpha-synuclein uptake and NLRP3 inflammasome activation in microglia J Exp Med 2019 216 6 1411 1430 10.1084/jem.20182191 31036561 PMC6547864 · DOI
  48. [52]Zhou Y Lu M Du RH MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease Mol Neurodegener 2016 11 28 10.1186/s13024-016-0094-3 27084336 PMC4833896 · DOI · Paper page
  49. [53]Pourcet B Zecchin M Ferri L Nuclear Receptor Subfamily 1 Group D Member 1 regulates circadian activity of NLRP3 inflammasome to reduce the severity of fulminant hepatitis in mice Gastroenterology 2018 154 5 1449 1464.e1420 10.1053/j.gastro.2017.12.019 29277561 PMC5892845 · DOI
  50. [54]Pariollaud M Gibbs JE Hopwood TW Circadian clock component REV-ERBalpha controls homeostatic regulation of pulmonary inflammation J Clin Invest 2018 128 6 2281 2296 10.1172/JCI93910 29533925 PMC5983347 · DOI
  51. [55]Reitz CJ Alibhai FJ Khatua TN SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome Commun Biol 2019 2 353 10.1038/s42003-019-0595-z 31602405 PMC6776554 · DOI

Authors
Kou, L., Chi, X., Sun, Y., Han, C., Wan, F., Hu, J., Yin, S., Wu, J., Li, Y., Zhou, Q., Zou, W., Xiong, N., Huang, J., Xia, Y., & Wang, T.
Affiliations
  • Huazhong University of Science and Technology (CN)
  • University of Science and Technology of China (CN)
  • Wuhan Union Hospital (CN)
Corresponding author
  • Xia, Yun
  • Wang, Tao
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2022-06-06
Volume
19
Issue
1
Pages
133-133
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-022-02494-y
PMC
PMC9169406
OpenAlex
W4281854361
Cited by
109
References
55
Citations by year
2026: 30 · 2025: 27 · 2024: 29 · 2023: 22 · 2022: 1
FWCI
6.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81671260, 81974201)
  • National Key Plan for Scientific Research and Development of China (2017YFC1310200, 2016YFC1306000)
  • Chinese Sleep Research Society Hansoh Project (2019HSA02)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
NR1D1, Parkinson's disease, circadian clock, NLRP3 inflammasome, microglial activation, neuroinflammation, neuroprotection, SR9009, NF-κB, microglial polarization, MPTP-induced neurotoxicity, substantia nigra, dopaminergic neuron loss, nigrostriatal pathway, alpha-synuclein fibrils, circadian rhythm
MeSH terms
Neuroprotection, NLR Family, Pyrin Domain-Containing 3 Protein, Neuroinflammatory Diseases, Animals, Mice, Inbred C57BL, Parkinson Disease, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Cytokines, NF-kappa B, Microglia, Mice, CLOCK Proteins, Circadian Clocks, Inflammasomes

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