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Treg Cells Attenuate Neuroinflammation and Protect Neurons in a Mouse Model of Parkinson’s Disease

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Abstract

Regulatory T cells (Tregs), which secrete transforming growth factor (TGF)-β and interleukin (IL)-10, have essential role in anti-inflammatory and neurotrophic functions. Herein, we explore the neuroprotection of Tregs in Parkinson’s disease (PD) by adoptive transfer of Tregs. Tregs, isolated by magnetic sorting, were activated in vitro and then were adoptively transferred to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-treated mice. Neuroinflammation, dopaminergic neuronal loss and behavioral changes of PD mice were evaluated. Live cell imaging system detected a dynamic contact of Tregs with MN9D cells that were stained with CD45 and galectin-1, respectively. Tregs prevented MPTP-induced dopaminergic neuronal loss, behavioral changes, and attenuated the inflammatory reaction in the brain. When blockade the LFA-1 activity in Tregs or the ICAM-1 activity in endothelial cells, the percentage of Tregs in substantia nigra (SN) decreased. CD45 and galectin-1 were expressed by Tregs and MN9D cells, respectively. CD45-labeled Tregs dynamically contacted with galectin-1-labeled MN9D cells. Inhibiting CD45 in Tregs impaired the ability of Tregs to protect dopaminergic neurons against MPP+ toxicity. Similarly, galectin-1 knockdown in MN9D cells reduced the ability of Tregs neuroprotection. Adoptive transfer of Tregs protects dopaminergic neurons in PD mice by a cell-to-cell contact mechanism underlying CD45-galectin-1 interaction.

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References

  • Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3:e2740

    PubMed  PubMed Central  Google Scholar 

  • Banks WA, Niehoff ML, Ponzio NM, Erickson MA, Zalcman SS (2012) Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice. J Neuroinflammation 9:231

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Yera D, Martinez-Pagan ME, de Pablos V, Fernandez-Villalba E, Herrero MT (2011) IFNgamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 2:e142

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bas J, Calopa M, Mestre M, Mollevi DG, Cutillas B, Ambrosio S, Buendia E (2001) Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism. J Neuroimmunol 113:146–152

    CAS  PubMed  Google Scholar 

  • Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11

    CAS  PubMed  Google Scholar 

  • Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376

    PubMed  PubMed Central  Google Scholar 

  • Blom C, Deller BL, Fraser DD, Patterson EK, Martin CM, Young BM, Liaw PC, Yazdan-Ashoori P, Ortiz A, Webb B, Kilmer G, Carter DE, Cepinskas G (2015) Human severe sepsis cytokine mixture increases β2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro. Crit Care 19:149

    PubMed  PubMed Central  Google Scholar 

  • Bohatschek M, Werner A, Raivich G (2001) Systemic LPS injection leads to granulocyte influx into normal and injured brain: effects of ICAM-1 deficiency. Exp Neurol 172:137–152

    CAS  PubMed  Google Scholar 

  • Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192

    CAS  PubMed  Google Scholar 

  • Cao JJ, Li KS, Shen YQ (2011) Activated immune cells in Parkinson’s disease. J NeuroImmune Pharmacol 6:323–329

    PubMed  Google Scholar 

  • Cederbom L, Hall H, Ivars F (2000) CD4+CD25+ regulatory T cells downregulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 30:1538–1543

    CAS  PubMed  Google Scholar 

  • Chung ES, Kim H, Lee G, Park S, Kim H, Bae H (2012) Neuro-protective effects of bee venom by suppression of neuroinflammatory responses in a mouse model of Parkinson’s disease: role of regulatory T cells. Brain Behav Immun 26:1322–1330

    CAS  PubMed  Google Scholar 

  • Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 5:137–143

    CAS  PubMed  Google Scholar 

  • Danikowski KM, Jayaraman S, Prabhakar BS (2017 Jun 9) Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation 14(1):117. https://doi.org/10.1186/s12974-017-0892-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faucheux BA, Bonnet AM, Agid Y, Hirsch EC (1999) Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 353:981–982

    CAS  PubMed  Google Scholar 

  • Gee JM, Kalil A, Thullbery M, Becker KJ (2008) Induction of immunologic tolerance to myelin basic protein prevents central nervous system autoimmunity and improves outcome after stroke. Stroke 39:1575–1582

    PubMed  PubMed Central  Google Scholar 

  • He J, Baum LG (2006) Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab Investig 86:578–590

    CAS  PubMed  Google Scholar 

  • Huang Y, Liu Z, Cao BB, Qiu YH, Peng YP (2017) Treg cells protect dopaminergic neurons against MPP+ neurotoxicity via CD47-SIRPA interaction. Cell Physiol Biochem 41:1240–1254

    CAS  PubMed  Google Scholar 

  • Ishibashi S, Kuroiwa T, Sakaguchi M, Sun L, Kadoya T, Okano H, Mizusawa H (2007) Galectin-1 regulates neurogenesis in the subventricular zone and promotes functional recovery after stroke. Exp Neurol 207:302–313

    CAS  PubMed  Google Scholar 

  • Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE (2013) GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol 265:1–10

    CAS  PubMed  Google Scholar 

  • Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999) MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson’s disease. Acta Neurobiol Exp 59:1–8

    CAS  Google Scholar 

  • Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–199

    CAS  PubMed  Google Scholar 

  • Lipowsky H (2012) The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases. Ann Biomed Eng 40:840–848

    PubMed  Google Scholar 

  • Liu Z, Chen HQ, Huang Y, Qiu YH, Peng YP (2016) Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. Brain Behav Immun 51:131–143

    CAS  PubMed  Google Scholar 

  • Liu Z, Huang Y, Cao BB, Qiu YH, Peng YP (2017) Th17 cells induce dopaminergic neuronal death via LFA-1/ICAM-1 interaction in a mouse model of Parkinson’s disease. Mol Neurobiol 54:7762–7776

    CAS  PubMed  Google Scholar 

  • Long-Smith CM, Collins L, Toulouse A, Sullivan AM, Nolan YM (2010) Interleukin-1beta contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro. J Neuroimmunol 226:20–26

    CAS  PubMed  Google Scholar 

  • Liu J, Gong N, Huang X, Reynolds AD, Mosley RL, and Gendelman HE (2009) Neuromodulatory Activities of CD4+CD25+ Regulatory T Cells in a Murine Model of HIV-1-Associated Neurodegeneration. The Journal of Immunology 182:3855-3865

  • Miklossy J, Doudet DD, Schwab C, Yu S, Mcgeer EG, McGeer PL (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197:275–283

    CAS  PubMed  Google Scholar 

  • Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13:668–677

    CAS  PubMed  Google Scholar 

  • Perillo NL, Pace KE, Seilhamer JJ, Baum LG (1995) Apoptosis of T cells mediated by galectin-1. Nature 378:736–739

    CAS  PubMed  Google Scholar 

  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462

    PubMed  PubMed Central  Google Scholar 

  • Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007) Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82:1083–1094

    CAS  PubMed  Google Scholar 

  • Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009a) Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells. J Proteome Res 8:3497–3511

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009b) Nitrated α-synucleininduced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182:4137–4149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 184:2261–2271

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, Gasser T, Stoltze L (2007) Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol 188:117–127

    CAS  PubMed  Google Scholar 

  • Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic selftolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    CAS  PubMed  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    CAS  PubMed  Google Scholar 

  • Sasaguri K, Yamada K, Narimatsu Y, Oonuki M, Oishi A, Koda K, Kubo K, Yamamoto T, Kadoya T (2016) Stress-induced galectin-1 influences immune tolerance in the spleen and thymus by modulating CD45 immunoreactive lymphocytes. J Physiol Sci 67:489–496. https://doi.org/10.1007/s12576-016-0478-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 116:1744–1754

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singer BD, King LS, D'Alessio FR (2014) Regulatory T cells as immunotherapy. Front Immunol 5:46

    PubMed  PubMed Central  Google Scholar 

  • Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190

    CAS  PubMed  Google Scholar 

  • Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 104:19446–19451

    CAS  PubMed  PubMed Central  Google Scholar 

  • Varatharaj A, Galea I (2016) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1–12

    PubMed  Google Scholar 

  • Wang H, Sun J, Goldstein H (2008) Human immunodeficiency virus type 1 infection increases the in vivo capacity of peripheral monocytes to cross the blood-brain barrier into the brain and the in vivo sensitivity of the blood-brain barrier to disruption by lipopolysaccharide. J Virol 82:7591–7600

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh H, Moore DJ, Markmann JF, Kim JI (2013) Mechanisms of regulatory T cell counter-regulation by innate immunity. Transplant Rev (Orlando) 27:61–64

    Google Scholar 

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Acknowledgements

This work was supported by grants 31771293 and 81701633 from the National Natural Science Foundation of China, grant 18B13 from Nantong University, grant BK20180948 from Natural Science Foundation of Jiangsu Province of China, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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  1. Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, China

    Yan Huang, Zhan Liu, Bei-Bei Cao, Yi-Hua Qiu & Yu-Ping Peng

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  1. Yan Huang
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  4. Yi-Hua Qiu
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Correspondence to Yi-Hua Qiu or Yu-Ping Peng.

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All of the experiments were performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and was approved by the Institutional Animal Care and Use Committee of Nantong University.

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Huang, Y., Liu, Z., Cao, BB. et al. Treg Cells Attenuate Neuroinflammation and Protect Neurons in a Mouse Model of Parkinson’s Disease. J Neuroimmune Pharmacol 15, 224–237 (2020). https://doi.org/10.1007/s11481-019-09888-5

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