Skip to main content
SpringerLink
Log in

Exosomes derived from regulatory T cells attenuates MPP+-induced inflammatory response and oxidative stress in BV-2 cells by inhibiting the TLR4/NF-κB signaling

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Parkinson’s disease (PD) is a common neurodegenerative disorder associated with microglia-mediated neuroinflammation in pathogenesis. Regulatory T cells (Treg cells) are involved in the regulation of microglia activation and neuroinflammation. However, it is yet to be established whether exosomes derived from Treg cells (Treg-Exos) possess protective effect against MPP+-induced inflammation and oxidative stress in microglia.

Objective

In our study, we examined the function of Treg cells in the in vitro PD model. MTT assay was used to assess the viability of BV2 cells. ROS, MDA, and SOD activity were detected, and ELISA was performed to estimate the inflammatory response and oxidative stress of BV-2 cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were applied to detect the level changes of genes involved in the TLR4/NF-κB signaling pathway.

Results

The results showed that Treg-Exos improved the cell viability of MPP+-treated BV2 cells. MPP+-induced increase in ROS and MDA production, as well as decrease in SOD activity in BV2 cells were attenuated by Treg-Exos. The increased levels of inflammatory cytokines IL-β, IL-6, and TNF-α in MPP+-induced BV2 cells were also prevented by the treatment of Treg-Exos. Treg-Exos inhibited MPP+-induced activation of the TLR4/NF-κB signaling, indicated by decreased protein level of TLR4 and p-p65/p65 ratio in BV2 cells. Further, we also found that upregulation of TLR4 blocks the protective effect of Treg-Exos on MPP+-treated BV2 cells.

Conclusions

Collectively, Treg-Exos attenuated MPP+-induced oxidative stress and inflammatory injury in BV-2 cells by inhibiting the TLR4/NF-κB signaling.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Chen T et al (2015) Donepezil regulates 1-methyl-4-phenylpyridinium-induced microglial polarization in Parkinson’s Disease. ACS Chem Neurosci 6:1708–1714

    Article  CAS  PubMed  Google Scholar 

  • Diller ML et al (2016) Balancing inflammation: the link between Th17 and regulatory T cells. Mediators Inflamm 2016:6309219

    Article  PubMed  PubMed Central  Google Scholar 

  • Duffy SS et al (2018) The role of regulatory T cells in nervous system pathologies. J Neurosci Res 96:951–968

    Article  CAS  PubMed  Google Scholar 

  • Haney MJ et al (2015) Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release 207:18–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hankittichai P et al (2020) Artocarpus lakoocha extract inhibits LPS-induced inflammatory response in RAW 264.7 macrophage cells. Int J Mol Sci 21:1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho MS (2019) Microglia in Parkinson’s Disease. Adv Exp Med Biol 1175:335–353

    Article  CAS  PubMed  Google Scholar 

  • Hu H et al (2020) Exosomes derived from regulatory T cells ameliorate acute myocardial infarction by promoting macrophage M2 polarization. IUBMB Life 72:2409–2419

    Article  CAS  PubMed  Google Scholar 

  • Huo W et al (2019) Imbalanced spinal infiltration of Th17/Treg cells contributes to bone cancer pain via promoting microglial activation. Brain Behav Immun 79:139–151

    Article  CAS  PubMed  Google Scholar 

  • Jagadeesan AJ et al (2017) Current trends in etiology, prognosis and therapeutic aspects of Parkinson’s disease: a review. Acta Biomed 88:249–262

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang L et al (2019) Exosomes in pathogenesis, diagnosis, and treatment of Alzheimer’s Disease. Med Sci Monit 25:3329–3335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King HW, Michael MZ, Gleadle JM (2012) Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12:421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai CP, Breakefield XO (2012) Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol 3:228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lakhal S, Wood MJ (2011) Exosome nanotechnology: an emerging paradigm shift in drug delivery: exploitation of exosome nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers. BioEssays 33:737–741

    Article  CAS  PubMed  Google Scholar 

  • Lee Y, El Andaloussi S, Wood MJ (2012) Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 21:R125-134

    Article  CAS  PubMed  Google Scholar 

  • Lee MB et al (2017) JQ1, a BET inhibitor, controls TLR4-induced IL-10 production in regulatory B cells by BRD4-NF-kappaB axis. BMB Rep 50:640–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao F, Lu X, Dong W (2020) Exosomes derived from T regulatory cells relieve inflammatory bowel disease by transferring miR-195a-3p. IUBMB Life 72

  • Liu WW et al (2020) BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson’s disease mouse model. FASEB J 34:6570–6581

    Article  CAS  PubMed  Google Scholar 

  • Lun P et al (2022) HOTTIP downregulation reduces neuronal damage and microglial activation in Parkinson’s disease cell and mouse models. Neural Regen Res 17:887–897

    Article  CAS  PubMed  Google Scholar 

  • Marogianni C et al (2020) Neurodegeneration and inflammation—an interesting interplay in Parkinson’s Disease. Int J Mol Sci 21:8421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell S, Vargas J, Hoffmann A (2016) Signaling via the NFkappaB system. Wiley Interdiscip Rev Syst Biol Med 8:227–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38:414–423

    Article  CAS  PubMed  Google Scholar 

  • Orihuela R, McPherson CA, Harry GJ (2016a) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665

    Article  CAS  PubMed  Google Scholar 

  • Pajares M et al (2020) Inflammation in Parkinson’s Disease: mechanisms and therapeutic implications. Cells 9:1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu Y et al (2019) JLX001 modulated the inflammatory reaction and oxidative stress in pMCAO rats via inhibiting the TLR2/4-NF-kappaB signaling pathway. Neurochem Res 44:1924–1938

    Article  CAS  PubMed  Google Scholar 

  • Qiu Z et al (2020) Dexmedetomidine inhibits neuroinflammation by altering microglial M1/M2 polarization through MAPK/ERK pathway. Neurochem Res 45:345–353

    Article  CAS  PubMed  Google Scholar 

  • Rahimifard M et al (2017) Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev 36:11–19

    Article  CAS  PubMed  Google Scholar 

  • Reus GZ et al (2015) The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300:141–154

    Article  CAS  PubMed  Google Scholar 

  • Schneider A, Simons M (2013) Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 352:33–47

    Article  CAS  PubMed  Google Scholar 

  • Simons M, Raposo G (2009) Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581

    Article  CAS  PubMed  Google Scholar 

  • Tysnes OB, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm (vienna) 124:901–905

    Article  PubMed  Google Scholar 

  • van den Boorn JG et al (2011) SiRNA delivery with exosome nanoparticles. Nat Biotechnol 29:325–326

    Article  PubMed  Google Scholar 

  • Vlassov AV et al (2012) Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 1820:940–948

    Article  CAS  PubMed  Google Scholar 

  • Wang L et al (2020) Acupuncture attenuates inflammation in microglia of vascular dementia rats by inhibiting miR-93-mediated TLR4/MyD88/NF-kappaB signaling pathway. Oxid Med Cell Longev 2020:8253904

    PubMed  PubMed Central  Google Scholar 

  • Wu X, Zheng T, Zhang B (2017) Exosomes in Parkinson’s Disease. Neurosci Bull 33:331–338

    Article  CAS  PubMed  Google Scholar 

  • Wu R et al (2019) Roles of exosomes derived from immune cells in cardiovascular diseases. Front Immunol 10:648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie L et al (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45:180–191

    Article  CAS  PubMed  Google Scholar 

  • Xu X et al (2020) Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-kappaB and TNF-alpha/TNFR1/NF-kappaB pathways. Br J Pharmacol 177:5224–5245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye Y et al (2019) Meisoindigo protects against focal cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome activation and regulating microglia/macrophage polarization via TLR4/NF-kappaB signaling pathway. Front Cell Neurosci 13:553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y et al (2018) TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson’s disease. Biochem Biophys Res Commun 499:797–802

    Article  CAS  PubMed  Google Scholar 

  • Zhi Z et al (2021) Sinensetin attenuates amyloid Beta25-35-induced oxidative stress, inflammation, and apoptosis in SH-SY5Y cells through the TLR4/NF-kappaB signaling pathway. Neurochem Res 46:3012–3024

    Article  CAS  PubMed  Google Scholar 

  • Zhou K et al (2017) Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J Cereb Blood Flow Metab 37:967–979

    Article  CAS  PubMed  Google Scholar 

  • Zusso M et al (2019) Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway. J Neuroinflammation 16:148

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

No funding.

Author information

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 41 Linyin Road, Kun District, Baotou, 014010, Inner Mongolia Autonomous Region, China

    Jun Liu, Junqing Zhang & Yuanyuan Ao

Authors
  1. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junqing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanyuan Ao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JL and YA performed experiments and wrote the manuscript. JZ analyzed data. YA supervised this project and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yuanyuan Ao.

Ethics declarations

Conflict of interest

Jun Liu declares that he has no conflict of interest. Junqing Zhang declares that he has no conflict of interest. Yuanyuan Ao declares that she has no conflict of interest.

Ethical approval

The article does not contain any studies with human and animal and this study was performed following institutional and national guidelines.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Zhang, J. & Ao, Y. Exosomes derived from regulatory T cells attenuates MPP+-induced inflammatory response and oxidative stress in BV-2 cells by inhibiting the TLR4/NF-κB signaling. Mol. Cell. Toxicol. 19, 283–291 (2023). https://doi.org/10.1007/s13273-022-00258-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-022-00258-6

Keywords

Search

Navigation