Skip to main content

Advertisement

SpringerLink
Log in

Formyl Peptide Receptor 1-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a chronic degenerative disease of the central nervous system that is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation. Unclear are the factors triggering gliosis and demyelination. New findings suggest an important role of the innate immune response in the initiation and progression of active demyelinating lesions. The innate immune response is induced by pathogen-associated or danger-associated molecular patterns, which are identified by pattern recognition receptors (PRRs), including the G-protein coupled with formyl peptide receptors (FPRs). Glial cells, the immune cells of the central nervous system, also express the PRRs. In this study, we used the cuprizone mice model to investigate the expression of the FPR1 in the course of cuprizone-induced demyelination In addition, we used FPR1-deficient mice to analyze glial cell activation through immunohistochemistry and real-time RT-PCR in cuprizone model. Our results revealed a significantly increased expression of FPR1 in the cortex of cuprizone-treated mice. FPR1-deficient mice showed a slight but significant decrease of demyelination in the corpus callosum compared to the wild-type mice. Furthermore, FPR1 deficiency resulted in reduced glial cell activation and mRNA expression of microglia/macrophages markers, as well as pro- and anti-inflammatory cytokines in the cortex, compared to wild-type mice after cuprizone-induced demyelination. Combined together, these results suggest that the FPR1 is an important part of the innate immune response in the course of cuprizone-induced demyelination.

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

Abbreviations

CC:

Corpus callosum

CX:

Cortex

FPR:

Formyl peptide receptor

GFAP:

Glial fibrillary acidic protein

Hc:

Hippocampus

Iba-1:

ionized calcium binding adaptor molecule 1

Itgam:

Integrin alpha M

KO:

Lnock out

PLP:

Proteolipid protein

WT:

Wild type

References

  • Acs P, Kipp M, Norkute A, Johann S, Clarner T, Braun A, Berente Z, Komoly S, Beyer C (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57:807–814

    Article  PubMed  Google Scholar 

  • Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468

    Article  PubMed  Google Scholar 

  • Barry A, Cronin O, Ryan AM et al (2016) Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology. Front Physiol 7:194

    Article  PubMed  PubMed Central  Google Scholar 

  • Brandenburg LO, Koch T, Sievers J, Lucius R (2007) Internalization of PrP106-126 by the formyl-peptide-receptor-like-1 in glial cells. J Neurochem 101:718–728

    Article  CAS  PubMed  Google Scholar 

  • Buschmann JP, Berger K, Awad H, Clarner T, Beyer C, Kipp M (2012) Inflammatory response and chemokine expression in the white matter corpus callosum and gray matter cortex region during cuprizone-induced demyelination. J Mol Neurosci 48:66–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308

    Article  CAS  PubMed  Google Scholar 

  • Cattaneo F, Guerra G, Ammendola R (2010) Expression and signaling of formyl-peptide receptors in the brain. Neurochem Res 35:2018–2026

    Article  CAS  PubMed  Google Scholar 

  • Cattaneo F, Parisi M, Ammendola R (2013) Distinct signaling cascades elicited by different formyl peptide receptor 2 (FPR2) agonists. Int J Mol Sci 14:7193–7230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen K, Le Y, Liu Y, Gong W, Ying G, Huang J, Yoshimura T, Tessarollo L, Wang JM (2010) A critical role for the g protein-coupled receptor mFPR2 in airway inflammation and immune responses. J Immunol 184:3331–3335

    Article  CAS  PubMed  Google Scholar 

  • Clarner T, Buschmann JP, Beyer C, Kipp M (2011a) Glial amyloid precursor protein expression is restricted to astrocytes in an experimental toxic model of multiple sclerosis. J Mol Neurosci 43:268–274

    Article  CAS  PubMed  Google Scholar 

  • Clarner T, Parabucki A, Beyer C, Kipp M (2011b) Corticosteroids impair remyelination in the corpus callosum of cuprizone-treated mice. J Neuroendocrinol 23:601–611

    Article  CAS  PubMed  Google Scholar 

  • Clarner T, Diederichs F, Berger K, Denecke B, Gan L, van der Valk P, Beyer C, Amor S, Kipp M (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia 60:1468–1480

    Article  PubMed  Google Scholar 

  • Draheim T, Liessem A, Scheld M, Wilms F, Weißflog M, Denecke B, Kensler TW, Zendedel A, Beyer C, Kipp M, Wruck CJ, Fragoulis A, Clarner T (2016) Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model. Glia 64(12):2219–2230. doi:10.1002/glia.23058

  • Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL (2016) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol. doi:10.1007/s12035-016-0245-0

  • Dufton N, Hannon R, Brancaleone V et al (2010) Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation. J Immunol 184:2611–2619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao JL, Chen H, Filie JD, Kozak CA, Murphy PM (1998) Differential expansion of the N-formylpeptide receptor gene cluster in human and mouse. Genomics 51:270–276

    Article  CAS  PubMed  Google Scholar 

  • Gao JL, Lee EJ, Murphy PM (1999) Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor. J Exp Med 189:657–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldberg J, Clarner T, Beyer C, Kipp M (2015) Anatomical distribution of cuprizone-induced lesions in C57BL6 mice. J Mol Neurosci 57:166–175

    Article  CAS  PubMed  Google Scholar 

  • Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 121:367–387

    Article  CAS  Google Scholar 

  • Hernandez-Pedro NY, Espinosa-Ramirez G, de la Cruz VP, Pineda B, Sotelo J (2013) Initial immunopathogenesis of multiple sclerosis: innate immune response. Clinical & developmental immunology 2013:413465

    Article  Google Scholar 

  • Hiremath MM, Chen VS, Suzuki K, Ting JP, Matsushima GK (2008) MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 203:23–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hochstrasser T, Exner GL, Nyamoya S, Schmitz C, Kipp M (2017) Cuprizone-containing pellets are less potent to induce consistent demyelination in the corpus callosum of C57BL/6 mice. J Mol Neurosci 61:617–624

    Article  CAS  PubMed  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  CAS  PubMed  Google Scholar 

  • Kilic AK, Esendagli G, Sayat G, Talim B, Karabudak R, Kurne AT (2015) Promotion of experimental autoimmune encephalomyelitis upon neutrophil granulocytes’ stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP) peptide. Autoimmunity 48:423–428

    Article  PubMed  Google Scholar 

  • Kipp M, Norkute A, Johann S et al (2008) Brain-region-specific astroglial responses in vitro after LPS exposure. J Mol Neurosci 35:235–243

    Article  CAS  PubMed  Google Scholar 

  • Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118:723–736

    Article  PubMed  Google Scholar 

  • Kipp M, Norkus A, Krauspe B, Clarner T, Berger K, van der Valk P, Amor S, Beyer C (2011) The hippocampal fimbria of cuprizone-treated animals as a structure for studying neuroprotection in multiple sclerosis. Inflamm Res 60:723–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kipp M, van der Valk P, Amor S (2012) Pathology of multiple sclerosis. CNS Neurol Disord Drug Targets 11:506–517

    Article  CAS  PubMed  Google Scholar 

  • Kipp M, Nyamoya S, Hochstrasser T, Amor S (2017) Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol 27(2):123–137. doi:10.1111/bpa.12454

  • Konat GW, Kielian T, Marriott I (2006) The role of Toll-like receptors in CNS response to microbial challenge. J Neurochem 99:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kutzelnigg A, Lassmann H (2014) Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol 122:15–58

    Article  PubMed  Google Scholar 

  • Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58:253–263

    PubMed  Google Scholar 

  • Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364:2106–2112

    Article  CAS  PubMed  Google Scholar 

  • Li L, Chen K, Xiang Y, Yoshimura T, Su S, Zhu J, Bian XW, Wang JM (2016) New development in studies of formyl-peptide receptors: critical roles in host defense. J Leukoc Biol 99:425–435

    Article  CAS  PubMed  Google Scholar 

  • Mariani MM, Kielian T (2009) Microglia in infectious diseases of the central nervous system. J NeuroImmune Pharmacol 4:448–461

    Article  PubMed  PubMed Central  Google Scholar 

  • Mayo L, Quintana FJ, Weiner HL (2012) The innate immune system in demyelinating disease. Immunol Rev 248:170–187

    Article  PubMed  PubMed Central  Google Scholar 

  • Merres J, Höss J, Albrecht LJ, Kress E, Soehnlein O, Jansen S, Pufe T, Tauber SC, Brandenburg LO (2013) Role of the cathelicidin-related antimicrobial peptide in inflammation and mortality in a mouse model of bacterial meningitis. J Innate Immun 6(2):205–218. doi:10.1159/000353645

  • Migeotte I, Communi D, Parmentier M (2006) Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses. Cytokine Growth Factor Rev 17:501–519

    Article  CAS  PubMed  Google Scholar 

  • Mishra MK, Yong VW (2016) Myeloid cells—targets of medication in multiple sclerosis. Nat Rev Neurol 12:539–551

    Article  CAS  PubMed  Google Scholar 

  • Muller-Ladner U, Jones JL, Wetsel RA, Gay S, Raine CS, Barnum SR (1996) Enhanced expression of chemotactic receptors in multiple sclerosis lesions. J Neurol Sci 144:135–141

    Article  CAS  PubMed  Google Scholar 

  • Oldekamp S, Pscheidl S, Kress E, Soehnlein O, Jansen S, Pufe T, Wang JM, Tauber SC, Brandenburg LO (2014) Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis. Immunology 143:447–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasquini LA, Calatayud CA, Bertone Una AL, Millet V, Pasquini JM, Soto EF (2007) The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochem Res 32:279–292

    Article  CAS  PubMed  Google Scholar 

  • Perrier S, Darakhshan F, Hajduch E (2006) IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? FEBS Lett 580:6289–6294

    Article  CAS  PubMed  Google Scholar 

  • Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skripuletz T, Lindner M, Kotsiari A, Garde N, Fokuhl J, Linsmeier F, Trebst C, Stangel M (2008) Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am J Pathol 172:1053–1061

    Article  PubMed  PubMed Central  Google Scholar 

  • Skripuletz T, Gudi V, Hackstette D, Stangel M (2011) De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol Histopathol 26:1585–1597

    CAS  PubMed  Google Scholar 

  • Skripuletz T, Hackstette D, Bauer K et al (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 136:147–167

    Article  PubMed  Google Scholar 

  • Slowik A, Merres J, Elfgen A, Jansen S, Mohr F, Wruck CJ, Pufe T, Brandenburg LO (2012) Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE) - and amyloid beta 1-42-induced signal transduction in glial cells. Mol Neurodegener 7:55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Star BJ, Vogel DY, Kipp M, Puentes F, Baker D, Amor S (2012) In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets 11:570–588

    Article  PubMed  Google Scholar 

  • van der Valk P, Amor S (2009) Preactive lesions in multiple sclerosis. Curr Opin Neurol 22:207–213

    PubMed  Google Scholar 

Download references

Acknowledgement

We thank Susanne Echterhagen and Lian Shen for the excellent technical assistance. This study was supported by the Else Kröner-Fresenius-Stiftung (LOB) and START-Program of the RWTH Aachen University (LOB).

Author information

Author notes

  1. Kai Bihler and Eugenia Kress contributed equally to this study

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Kai Bihler, Eugenia Kress, Stefan Esser, Thomas Pufe & Lars-Ove Brandenburg

  2. Institute of Neuroanatomy, RWTH Aachen University, Aachen, Germany

    Stella Nyamoya & Tim Clarner

  3. Department of Neurology, RWTH University Hospital Aachen, Aachen, Germany

    Simone C. Tauber

  4. Department of Urology, University Medicine Greifswald, Greifswald, Germany

    Matthias B. Stope

Authors
  1. Kai Bihler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugenia Kress
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Esser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stella Nyamoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simone C. Tauber
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tim Clarner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthias B. Stope
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Pufe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lars-Ove Brandenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars-Ove Brandenburg.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bihler, K., Kress, E., Esser, S. et al. Formyl Peptide Receptor 1-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination. J Mol Neurosci 62, 232–243 (2017). https://doi.org/10.1007/s12031-017-0924-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-017-0924-y

Keywords

Search

Navigation