Skip to main content
SpringerLink
Log in

Resveratrol-mediated reversal of changes in purinergic signaling and immune response induced by Toxoplasma gondii infection of neural progenitor cells

  • Original Article
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

The effects of Toxoplasma gondii during embryonic development have not been explored despite the predilection of this parasite for neurons and glial cells. Here, we investigated the activation of the purinergic system and proinflammatory responses during congenital infection by T. gondii. Moreover, neuroprotective and neuromodulatory properties of resveratrol (RSV), a polyphenolic natural compound, were studied in infected neuronal progenitor cells (NPCs). For this study, NPCs were isolated from the telencephalon of infected mouse embryos and subjected to neurosphere culture in the presence of EGF and FGF2. ATP hydrolysis and adenosine deamination by adenosine deaminase activity were altered in conditions of T. gondii infection. P2X7 and adenosine A2A receptor expression rates were augmented in infected NPCs together with an increase of proinflammatory (INF-γ and TNF-α) and anti-inflammatory (IL-10) cytokine gene expression. Our results confirm that RSV counteracted T. gondii-promoted effects on enzymes hydrolyzing extracellular nucleotides and nucleosides and also upregulated P2X7 and A2A receptor expression and activity, modulating INF-γ, TNF-α, and IL-10 cytokine production, which plays an integral role in the immune response against T. gondii.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dubey JP, Jones JL (2008) Toxoplasma gondii infection in humans and animals in the United States. Int J Parasitol 38:1257–1278

    Article  CAS  PubMed  Google Scholar 

  2. Lüder CGK, Giraldo-Velásquez M, Sendtner M, Gross U (1999) Toxoplasma gondii in primary rat CNS cells: differential contribution of neurons, astrocytes, and microglial cells for the intracerebral development and stage differentiation. Exp Parasitol 93:23–32. https://doi.org/10.1006/expr.1999.4421

    Article  PubMed  Google Scholar 

  3. Parlog A, Schlüter D, Dunay IR (2015) Toxoplasma gondii-induced neuronal alterations. Parasite Immunol 37:159–170

    Article  CAS  PubMed  Google Scholar 

  4. Cabral CM, Tuladhar S, Dietrich HK, Nguyen E, MacDonald WR, Trivedi T et al (2016) Neurons are the primary target cell for the brain-tropic intracellular parasite Toxoplasma gondii. PLoS Pathog 12(2):e1005447. https://doi.org/10.1371/journal.ppat.1005447

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Chao CC, Hu SX, Gekker G et al (1993) Effects of cytokines on multiplication of Toxoplasma-gondii in microglial cells. J Immunol 150:3404–3410

    CAS  PubMed  Google Scholar 

  6. Gaddi PJ, Yap GS (2007) Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol 85:155–159

    Article  CAS  PubMed  Google Scholar 

  7. Yarovinsky F, Kanzler H, Hieny S, Coffman RL, Sher A (2006) Toll-like receptor recognition regulates Immunodominance in an antimicrobial CD4+ T cell response. Immunity 25:655–664. https://doi.org/10.1016/j.immuni.2006.07.015

    Article  CAS  PubMed  Google Scholar 

  8. Burnstock G, Boeynaems JM (2014) Purinergic signalling and immune cells. Purinergic Signal 10:529–564

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Coutinho-Silva R, Monteiro da Cruz C, Persechini PM, Ojcius DM (2007) The role of P2 receptors in controlling infections by intracellular pathogens. Purinergic Signal 3:83–90

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Coutinho-Silva R, Ojcius DM (2012) Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites. Microbes Infect 14:1271–1277. https://doi.org/10.1016/j.micinf.2012.05.009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Corrêa G, Marques da Silva C, de Abreu Moreira-Souza AC, Vommaro RC, Coutinho-Silva R (2010) Activation of the P2X7 receptor triggers the elimination of Toxoplasma gondii tachyzoites from infected macrophages. Microbes Infect 12:497–504. https://doi.org/10.1016/j.micinf.2010.03.004

    Article  CAS  PubMed  Google Scholar 

  12. Thiel M, Caldwell CC, Sitkovsky MV (2003) The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect 5:515–526. https://doi.org/10.1016/S1286-4579(03)00068-6

    Article  CAS  PubMed  Google Scholar 

  13. Tonin AA, Da Silva AS, Casali EA et al (2014) Influence of infection by Toxoplasma gondii on purine levels and E-ADA activity in the brain of mice experimentally infected mice. Exp Parasitol 142:51–58. https://doi.org/10.1016/j.exppara.2014.04.008

    Article  CAS  PubMed  Google Scholar 

  14. Frémont L (2000) Biological effects of resveratrol. Life Sci 66:663–673. https://doi.org/10.1089/152308601317203567

    Article  PubMed  Google Scholar 

  15. Burns J, Yokota T, Ashihara H, Lean MEJ, Crozier A (2002) Plant foods and herbal sources of resveratrol. J Agric Food Chem 50:3337–3340. https://doi.org/10.1021/jf0112973

    Article  CAS  PubMed  Google Scholar 

  16. Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6:168–173. https://doi.org/10.2174/187152807781696464

    Article  CAS  PubMed  Google Scholar 

  17. Meng XL, Yang JY, Chen GL, Wang LH, Zhang LJ, Wang S, Li J, Wu CF (2008) Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure-activity relationships. Chem Biol Interact 174:51–59. https://doi.org/10.1016/j.cbi.2008.04.015

    Article  CAS  PubMed  Google Scholar 

  18. Kumar V, Pandey A, Jahan S, Shukla RK, Kumar D, Srivastava A, Singh S, Rajpurohit CS, Yadav S, Khanna VK, Pant AB (2016) Differential responses of trans-resveratrol on proliferation of neural progenitor cells and aged rat hippocampal neurogenesis. Sci Rep 6. https://doi.org/10.1038/srep28142

  19. Bottari NB, Baldissera MD, Tonin AA, Rech VC, Nishihira VSK, Thomé GR, Camillo G, Vogel FF, Duarte MMMF, Schetinger MRC, Morsch VM, Tochetto C, Fighera R, da Silva AS (2015) Effects of sulfamethoxazole-trimethoprim associated to resveratrol on its free form and complexed with 2-hydroxypropyl-β-cyclodextrin on cytokines levels of mice infected by toxoplasma gondii. Microb Pathog 87:40–44. https://doi.org/10.1016/j.micpath.2015.07.013

    Article  CAS  PubMed  Google Scholar 

  20. Hutton SR, Pevny LH (2008) Isolation, culture, and differentiation of progenitor cells from the central nervous system. Cold Spring Harb Protoc 3. https://doi.org/10.1101/pdb.prot5077

  21. Bottari NB, Schetinger MR, Pillat MM et al (2018) Resveratrol as a therapy to restore neurogliogenesis of neural progenitor cells infected by Toxoplasma gondii. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1180-z

  22. Pillat MM, Cheffer A, de Andrade CM, Morsch VM, Schetinger MRC, Ulrich H (2015) Bradykinin-induced inhibition of proliferation rate during neurosphere differentiation: consequence or cause of neuronal enrichment? Cytom Part A 87:929–935. https://doi.org/10.1002/cyto.a.22705

    Article  CAS  Google Scholar 

  23. Lunkes GI, Lunkes D, Stefanello F, Morsch A, Morsch VM, Mazzanti CM, Schetinger MRC (2003) Enzymes that hydrolyze adenine nucleotides in diabetes and associated pathologies. Thromb Res 109:189–194. https://doi.org/10.1016/S0049-3848(03)00178-6

    Article  CAS  PubMed  Google Scholar 

  24. Heymann D, Reddington M, Kreutzberg GW (1984) Subcellular localization of 5′-nucleotidase in rat brain. J Neurochem 43:971–978. https://doi.org/10.1111/j.1471-4159.1984.tb12832.x

    Article  CAS  PubMed  Google Scholar 

  25. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein dye binding. Anal Biochem 72:248–254. https://doi.org/10.1016/0003-2697(76)90527-3

    Article  CAS  Google Scholar 

  26. Guist G, Galanti B (1984) Colorimetric method. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim, pp 315–323

    Google Scholar 

  27. Schott KL, Assmann CE, Barbisan F, Azzolin VF, Bonadiman B, Duarte MMMF, Machado AK, da Cruz IBM (2017) Superoxide-hydrogen peroxide genetic imbalance modulates differentially the oxidative metabolism on human peripheral blood mononuclear cells exposed to seleno-L-methionine. Chem Biol Interact 273:18–27. https://doi.org/10.1016/j.cbi.2017.05.007

    Article  CAS  PubMed  Google Scholar 

  28. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4

    Article  CAS  PubMed  Google Scholar 

  29. Mendez OA, Koshy AA (2017) Toxoplasma gondii: entry, association, and physiological influence on the central nervous system. PLoS Pathog 13:e1006351

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Mishra SK, Braun N, Shukla V (2006) Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation. Develop 133:675–684. https://doi.org/10.1242/dev.02233

    Article  CAS  Google Scholar 

  31. Bureau G, Longpré F, Martinoli MG (2008) Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. J Neurosci Res 86:403–410. https://doi.org/10.1002/jnr.21503

    Article  CAS  PubMed  Google Scholar 

  32. Sun AY, Wang Q, Simonyi A, Sun GY (2010) Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol 41:375–383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492. https://doi.org/10.1007/978-3-642-28863-0_5

    Article  CAS  PubMed  Google Scholar 

  34. Fredholm BB, Cunha RA, Svenningsson P (2003) Pharmacology of adenosine A2A receptors and therapeutic applications. Curr Top Med Chem 3:413–426

    Article  CAS  PubMed  Google Scholar 

  35. Lappas CM, Rieger JM, Linden J (2005) A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073–1080. https://doi.org/10.4049/jimmunol.174.2.1073

    Article  CAS  PubMed  Google Scholar 

  36. Ferrari D, Chiozzi P, Falzoni S, Hanau S, di Virgilio F (1997) Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185:579–582. https://doi.org/10.1084/jem.185.3.579

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Zhang F, Wang H, Wu Q, Lu Y, Nie J, Xie X, Shi J (2013) Resveratrol protects cortical neurons against microglia-mediated neuroinflammation. Phyther Res 27:344–349. https://doi.org/10.1002/ptr.4734

    Article  CAS  Google Scholar 

  38. Bi XL, Yang JY, Dong YX, Wang JM, Cui YH, Ikeshima T, Zhao YQ, Wu CF (2005) Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia. Int Immunopharmacol 5:185–193. https://doi.org/10.1016/j.intimp.2004.08.008

    Article  CAS  PubMed  Google Scholar 

Download references

Financial support

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROEX, process number 88887.186030/2018-00). HU is grateful for grant support by the São Paulo State Foundation FAPESP (Project No. 2012/50880-4) and the National Research Council CNPq. MMP is grateful for a post-doctorate fellowship granted by FAPESP (Project No. 2015/19478-3).

Author information

Authors and Affiliations

  1. Graduate Program in Toxicological Biochemical and Department of Biochemistry and Molecular Biology, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil

    Nathieli B. Bottari, Maria R.C. Schetinger, Karine P. Reichert, Vanessa Machado, Charles E. Assmann, Anielen Dutra, Vera M. Morsch, Taís Vidal, Cinthia Melazzo & Aleksandro Schafer Da Silva

  2. Department of Animal Science, University of Santa Catarina State, 680 D, Rua Beloni Trombeta Zanin, Chapecó, SC, 89815-630, Brazil

    Nathieli B. Bottari & Aleksandro Schafer Da Silva

  3. Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo (USP), São Paulo, SP, Brazil

    Micheli M. Pillat & Henning Ulrich

  4. Graduate Program in Pharmacology, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil

    Ivana B. M. Da Cruz

  5. Graduate Program in Animal Science, Universidade do Estado de Santa Catarina (UDESC), Chapecó, SC, Brazil

    Aleksandro Schafer Da Silva

Authors
  1. Nathieli B. Bottari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Micheli M. Pillat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria R.C. Schetinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karine P. Reichert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vanessa Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles E. Assmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Henning Ulrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anielen Dutra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vera M. Morsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Taís Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ivana B. M. Da Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cinthia Melazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Aleksandro Schafer Da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nathieli B. Bottari, Micheli M. Pillat or Aleksandro Schafer Da Silva.

Ethics declarations

Ethics’ committee approval

This experiment was approved by the Ethics’ Committee for Animal Experimentation of the Universidade Federal de Santa Maria (UFSM), under protocol number 9509010915.

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Fig. S1

(DOCX 940 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bottari, N.B., Pillat, M.M., Schetinger, M.R. et al. Resveratrol-mediated reversal of changes in purinergic signaling and immune response induced by Toxoplasma gondii infection of neural progenitor cells. Purinergic Signalling 15, 77–84 (2019). https://doi.org/10.1007/s11302-018-9634-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-018-9634-3

Keywords

Search

Navigation