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Journal of Neuroinflammation

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01-12-2020 | Parkinson's Disease | Research

Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

Authors: Ying Liu, Lijia Yu, Yaling Xu, Xiaohui Tang, Xijin Wang

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Background

Smad3 signaling is indicated to regulate microglia activity. Parkinson’s disease (PD) neurodegeneration is shown to be associated with aging and neuroinflammation. However, it remains unclear about the relationship among Smad3 signaling, aging, neuroinflammation, and PD.

Methods

Rats were treated with SIS3 (a specific inhibitor of Smad3, intranigal injection) and/or lipopolysaccharide (intraperitoneal injection). We investigated the effect of SIS3 and lipopolysaccharide and their mechanism of action on motor behavior and nigrostriatal dopaminergic system in the rats. Furthermore, we explored the effect of SIS3 and LPS and their potential signaling mechanism of action on inflammatory response by using primary microglial cultures. Finally, we investigated the relationship among aging, Smad3 signaling, and neuroinflammation using animals of different ages.

Results

Both SIS3 and lipopolysaccharide induced significant behavior deficits and nigrostriatal dopaminergic neurodegeneration in the rats compared with the vehicle-treated (control) rats. Significantly increased behavior deficits and nigrostriatal dopaminergic neurodegeneration were observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the rats treated with vehicle, SIS3, or lipopolysaccharide. Furthermore, both SIS3 and lipopolysaccharide induced significant microglia activation and proinflammatory factor (IL-1β, IL-6, iNOS, and ROS) level increase in the SN of rats compared with the control rats. Significantly enhanced microglial inflammatory response was observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the other three groups. For our in vitro study, both SIS3 and lipopolysaccharide induced significant proinflammatory factor level increase in primary microglia cultures compared with the control cultures. Significantly increased inflammatory response was observed in the cultures co-treated with SIS3 and lipopolysaccharide compared with the other three groups. MAPK (ERK/p38) contributed to microglial inflammatory response induced by co-treatment with SIS3 and lipopolysaccharide. Interestingly, there was decrease in Smad3 and pSmad3 expression (protein) and enhancement of neuroinflammation in the mouse SN with aging. Proinflammatory factor levels were significantly inversely correlated with Smad3 and pSmad3 expression.

Conclusion

Our study strongly indicates the involvement of SN Smad3 signaling deficiency in aging and PD neurodegeneration and provides a novel molecular mechanism underlying the participation of aging in PD and helps to elucidate the mechanisms for the combined effect of multiple factors in PD.

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Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.PubMedCrossRef

Liu Z, Qiu AW, Huang Y, Yang Y, Chen JN, Gu TT, Cao BB, Qiu YH, Peng YP. IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson’s disease. Brain Behav Immun. 2019;81:630–45.PubMedCrossRef

Collier TJ, Kanaan NM, Kordower JH. Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates. Nat Rev Neurosci. 2011;12:359–66.PubMedPubMedCentralCrossRef

Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583–90.PubMedCrossRef

Richter F, Gabby L, McDowell KA, Mulligan CK, De La Rosa K, Sioshansi PC, Mortazavi F, Cely I, Ackerson LC, Tsan L, et al. Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. Neurobiol Aging. 2017;51:54–66.PubMedCrossRef

Kidd PM. Parkinson’s disease as multifactorial oxidative neurodegeneration: implications for integrative management. Altern Med Rev. 2000;5:502–29.PubMed

Zheng W, He R, Yan Z, Huang Y, Huang W, Cai Z, Su Y, Liu S, Deng Y, Wang Q, Xie H. Regulation of immune-driven pathogenesis in Parkinson’s disease by gut microbiota. Brain Behav Immun. 2020.

Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci. 2007;30:244–50.PubMedCrossRef

Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8:382–97.PubMedCrossRef

10.

Appel SH. CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest. 2009;119:13–5.PubMed

11.

Fan Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y, Ma JH, Wang XM. Systemic activation of NLRP3 inflammasome and plasma alpha-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuroinflammation. 2020;17:11.PubMedPubMedCentralCrossRef

12.

Lu J, Dou F, Yu Z. The potassium channel KCa3.1 represents a valid pharmacological target for microgliosis-induced neuronal impairment in a mouse model of Parkinson’s disease. J Neuroinflammation. 2019;16:273.PubMedPubMedCentralCrossRef

13.

Zhou Y, Wang G, Li D, Wang Y, Wu Q, Shi J, Zhang F. Dual modulation on glial cells by tetrahydroxystilbene glucoside protects against dopamine neuronal loss. J Neuroinflammation. 2018;15:161.PubMedPubMedCentralCrossRef

14.

Xu L, He D, Bai Y. Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol. 2016;53:6709–15.PubMedCrossRef

15.

Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener. 2015;4:19.PubMedPubMedCentralCrossRef

16.

Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 2000;19:1745–54.PubMedPubMedCentralCrossRef

17.

Vivien D, Ali C. Transforming growth factor-beta signalling in brain disorders. Cytokine Growth Factor Rev. 2006;17:121–8.PubMedCrossRef

18.

McMillin M, Grant S, Frampton G, Petrescu AD, Williams E, Jefferson B, Thomas A, Brahmaroutu A, DeMorrow S. Elevated circulating TGFbeta1 during acute liver failure activates TGFbetaR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice. J Neuroinflammation. 2019;16:69.PubMedPubMedCentralCrossRef

19.

Spittau B, Wullkopf L, Zhou X, Rilka J, Pfeifer D, Krieglstein K. Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro. Glia. 2013;61:287–300.PubMedCrossRef

20.

Patel RK, Prasad N, Kuwar R, Haldar D, Abdul-Muneer PM. Transforming growth factor-beta 1 signaling regulates neuroinflammation and apoptosis in mild traumatic brain injury. Brain Behav Immun. 2017;64:244–58.PubMedCrossRef

21.

Chen X, Liu Z, Cao BB, Qiu YH, Peng YP. TGF-beta1 neuroprotection via inhibition of microglial activation in a rat model of Parkinson’s disease. J NeuroImmune Pharmacol. 2017;12:433–46.PubMedCrossRef

22.

Abutbul S, Shapiro J, Szaingurten-Solodkin I, Levy N, Carmy Y, Baron R, Jung S, Monsonego A. TGF-beta signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia. 2012;60:1160–71.PubMedCrossRef

23.

Tichauer JE, von Bernhardi R. Transforming growth factor-beta stimulates beta amyloid uptake by microglia through Smad3-dependent mechanisms. J Neurosci Res. 2012;90:1970–80.PubMedCrossRef

24.

Flores B, von Bernhardi R. Transforming growth factor beta1 modulates amyloid beta-induced glial activation through the Smad3-dependent induction of MAPK phosphatase-1. J Alzheimers Dis. 2012;32:417–29.PubMedCrossRef

25.

Le Y, Iribarren P, Gong W, Cui Y, Zhang X, Wang JM. TGF-beta1 disrupts endotoxin signaling in microglial cells through Smad3 and MAPK pathways. J Immunol. 2004;173:962–8.PubMedCrossRef

26.

Tichauer JE, Flores B, Soler B, Eugenin-von Bernhardi L, Ramirez G, von Bernhardi R. Age-dependent changes on TGFbeta1 Smad3 pathway modify the pattern of microglial cell activation. Brain Behav Immun. 2014;37:187–96.PubMedCrossRef

27.

Hou L, Le G, Lin Z, Qian G, Gan F, Gu C, Jiang S, Mu J, Ge L, Huang K. Nontoxic concentration of ochratoxin A decreases the dosage of cyclosporine A to induce chronic nephropathy model via autophagy mediated by toll-like receptor 4. Cell Death Dis. 2020;11:153.PubMedPubMedCentralCrossRef

28.

Yan A, Zhang Y, Lin J, Song L, Wang X, Liu Z. Partial depletion of peripheral M1 macrophages reverses motor deficits in MPTP-treated mouse by suppressing neuroinflammation and dopaminergic neurodegeneration. Front Aging Neurosci. 2018;10:160.PubMedPubMedCentralCrossRef

29.

Wang J, Lai S, Li G, Zhou T, Wang B, Cao F, Chen T, Zhang X, Chen Y. Microglial activation contributes to depressive-like behavior in dopamine D3 receptor knockout mice. Brain Behav Immun. 2020;83:226–38.PubMedCrossRef

30.

Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK. The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. J Biol Chem. 2004;279:32626–32.PubMedCrossRef

31.

Qin S, Yang C, Huang W, Du S, Mai H, Xiao J, Lu T. Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-kappaB signaling pathways in LPS-activated BV-2 microglia. Pharmacol Res. 2018;133:218–35.PubMedCrossRef

32.

Ren M, Guo Y, Wei X, Yan S, Qin Y, Zhang X, Jiang F, Lou H. TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson’s disease. Exp Neurol. 2018;302:205–13.PubMedCrossRef

33.

Shen WC, Liang CJ, Huang TM, Liu CW, Wang SH, Young GH, Tsai JS, Tseng YC, Peng YS, Wu VC, Chen YL. Indoxyl sulfate enhances IL-1beta-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFkappaB/AP-1 pathway. Arch Toxicol. 2016;90:2779–92.PubMedCrossRef

34.

Sharma N, Nehru B. Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int. 2015;87:92–105.PubMedCrossRef

35.

Todd L, Palazzo I, Squires N, Mendonca N, Fischer AJ. BMP- and TGFbeta-signaling regulate the formation of Muller glia-derived progenitor cells in the avian retina. Glia. 2017;65:1640–55.PubMedPubMedCentralCrossRef

36.

Park T, Chen H, Kevala K, Lee JW, Kim HY. N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling. J Neuroinflammation. 2016;13:284.PubMedPubMedCentralCrossRef

37.

Kim WK, Hwang SY, Oh ES, Piao HZ, Kim KW, Han IO. TGF-beta1 represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity. J Immunol. 2004;172:7015–23.PubMedCrossRef

38.

Xie D, Ge X, Ma Y, Tang J, Wang Y, Zhu Y, Gao C, Pan S. Clemastine improves hypomyelination in rats with hypoxic-ischemic brain injury by reducing microglia-derived IL-1beta via P38 signaling pathway. J Neuroinflammation. 2020;17:57.PubMedPubMedCentralCrossRef

39.

Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7th ed. Cambridge: Academic Press; 2013.

40.

Mendes-Oliveira J, Lopes Campos F, Videira RA, Baltazar G. GPER activation is effective in protecting against inflammation-induced nigral dopaminergic loss and motor function impairment. Brain Behav Immun. 2017;64:296–307.PubMedCrossRef

41.

Bao LH, Zhang YN, Zhang JN, Gu L, Yang HM, Huang YY, Xia N, Zhang H. Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease. J Neuroinflammation. 2018;15:131.PubMedPubMedCentralCrossRef

42.

Pan B, Zhang H, Cui T, Wang X. TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux. J Mol Cell Cardiol. 2017;113:51–62.PubMedPubMedCentralCrossRef

43.

Pan B, Lewno MT, Wu P, Wang X. Highly dynamic changes in the activity and regulation of macroautophagy in hearts subjected to increased proteotoxic stress. Front Physiol. 2019;10:758.PubMedPubMedCentralCrossRef

44.

Pan B, Yang L, Wang J, Wang Y, Wang J, Zhou X, Yin X, Zhang Z, Zhao D. C-Abl tyrosine kinase mediates neurotoxic prion peptide-induced neuronal apoptosis via regulating mitochondrial homeostasis. Mol Neurobiol. 2014;49:1102–16.PubMedCrossRef

45.

Pan Y, Sun L, Wang J, Fu W, Fu Y, Wang J, Tong Y, Pan B. STI571 protects neuronal cells from neurotoxic prion protein fragment-induced apoptosis. Neuropharmacology. 2015;93:191–8.PubMedCrossRef

46.

Pan B, Li J, Parajuli N, Tian Z, Wu P, Lewno MT, Zou J, Wang W, Bedford L, Mayer RJ, et al. The calcineurin-TFEB-p62 pathway mediates the activation of cardiac macroautophagy by proteasomal malfunction. Circ Res. 2020;127:502–18.PubMedCrossRefPubMedCentral

47.

Jinnin M, Ihn H, Tamaki K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2006;69:597–607.PubMedCrossRef

48.

Yousif NM, de Oliveira ACP, Brioschi S, Huell M, Biber K, Fiebich BL. Activation of EP2 receptor suppresses poly(I: C) and LPS-mediated inflammation in primary microglia and organotypic hippocampal slice cultures: contributing role for MAPKs. Glia. 2018;66:708–24.PubMedCrossRef

49.

Lacroix S, Feinstein D, Rivest S. The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations. Brain Pathol. 1998;8:625–40.PubMedCrossRef

50.

Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.PubMedCrossRef

51.

Wang Q, He Q, Chen Y, Shao W, Yuan C, Wang Y. JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss. J Neuroinflammation. 2018;15:184.PubMedPubMedCentralCrossRef

52.

Wang J, Zhao D, Pan B, Fu Y, Shi F, Kouadir M, Yang L, Yin X, Zhou X. Toll-like receptor 2 deficiency shifts PrP106-126-induced microglial activation from a neurotoxic to a neuroprotective phenotype. J Mol Neurosci. 2015;55:880–90.PubMedCrossRef

53.

Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.PubMedCrossRef

54.

Cogut V, Bruintjes JJ, Eggen BJL, van der Zee EA, Henning RH. Brain inflammatory cytokines and microglia morphology changes throughout hibernation phases in Syrian hamster. Brain Behav Immun. 2018;68:17–22.PubMedCrossRef

55.

Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–69.PubMedPubMedCentralCrossRef

56.

Kanamaru Y, Sumiyoshi K, Ushio H, Ogawa H, Okumura K, Nakao A. Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis. J Immunol. 2005;174:4193–7.PubMedCrossRef

57.

Sugiyama Y, Kakoi K, Kimura A, Takada I, Kashiwagi I, Wakabayashi Y, Morita R, Nomura M, Yoshimura A. Smad2 and Smad3 are redundantly essential for the suppression of iNOS synthesis in macrophages by regulating IRF3 and STAT1 pathways. Int Immunol. 2012;24:253–65.PubMedCrossRef

58.

Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999;18:1280–91.PubMedPubMedCentralCrossRef

59.

Tapia-Gonzalez S, Giraldez-Perez RM, Cuartero MI, Casarejos MJ, Mena MA, Wang XF, Sanchez-Capelo A. Dopamine and alpha-synuclein dysfunction in Smad3 null mice. Mol Neurodegener. 2011;6:72.PubMedPubMedCentralCrossRef

60.

Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem. 1999;274:35053–8.PubMedCrossRef

61.

Wender R, Brown AM, Fern R, Swanson RA, Farrell K, Ransom BR. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci. 2000;20:6804–10.PubMedPubMedCentralCrossRef

62.

Wang XJ, Zhang S, Yan ZQ, Zhao YX, Zhou HY, Wang Y, Lu GQ, Zhang JD. Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK. Free Radic Biol Med. 2011;50:1094–106.PubMedCrossRef

63.

Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1–7.PubMedCrossRef

64.

Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–70.PubMedCrossRef

65.

Mittelbronn M, Dietz K, Schluesener HJ, Meyermann R. Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 2001;101:249–55.PubMedCrossRef

66.

Drechsel DA, Patel M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med. 2008;44:1873–86.PubMedPubMedCentralCrossRef

67.

von Bernhardi R, Tichauer JE, Eugenin J. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem. 2010;112:1099–114.CrossRef

68.

Jenner P, Olanow CW. Understanding cell death in Parkinson’s disease. Ann Neurol. 1998;44:S72–84.PubMedCrossRef

69.

Hou Y, Zhang Y, Mi Y, Wang J, Zhang H, Xu J, Yang Y, Liu J, Ding L, Yang J, et al. A novel quinolyl-substituted analogue of resveratrol inhibits LPS-induced inflammatory responses in microglial cells by blocking the NF-kappaB/MAPK signaling pathways. Mol Nutr Food Res. 2019;63:e1801380.PubMedCrossRef

70.

Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia. 2005;51:98–110.PubMedCrossRef

71.

Liu RP, Zou M, Wang JY, Zhu JJ, Lai JM, Zhou LL, Chen SF, Zhang X, Zhu JH. Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J Neuroinflammation. 2014;11:47.PubMedPubMedCentralCrossRef

72.

Du RH, Sun HB, Hu ZL, Lu M, Ding JH, Hu G. Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease. Cell Death Dis. 2018;9:404.PubMedPubMedCentralCrossRef

73.

Tang PM, Zhou S, Meng XM, Wang QM, Li CJ, Lian GY, Huang XR, Tang YJ, Guan XY, Yan BP, et al. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development. Nat Commun. 2017;8:14677.PubMedPubMedCentralCrossRef

74.

Kiefer R, Streit WJ, Toyka KV, Kreutzberg GW, Hartung HP. Transforming growth factor-beta 1: a lesion-associated cytokine of the nervous system. Int J Dev Neurosci. 1995;13:331–9.PubMedCrossRef

75.

Ye J, Yan H, Xia Z. Oxycodone ameliorates the inflammatory response induced by lipopolysaccharide in primary microglia. J Pain Res. 2018;11:1199–207.PubMedPubMedCentralCrossRef

76.

Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med. 2002;8:600–6.PubMedCrossRef

77.

d'Avila JC, Siqueira LD, Mazeraud A, Azevedo EP, Foguel D, Castro-Faria-Neto HC, Sharshar T, Chretien F, Bozza FA. Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation. J Neuroinflammation. 2018;15:28.PubMedPubMedCentralCrossRef

Title: Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK
Authors: Ying Liu
Lijia Yu
Yaling Xu
Xiaohui Tang
Xijin Wang
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Parkinson's Disease
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-02023-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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