Skip to main content
SpringerLink
Log in

An ανβ3 Integrin-Binding Peptide Ameliorates Symptoms of Chronic Progressive Experimental Autoimmune Encephalomyelitis by Alleviating Neuroinflammatory Responses in Mice

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

MOG35-55 triggers chronic, progressive experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, and the clinical course of EAE in this model is characterized by macrophage infiltration, axonal demyelination/damage, and progressive paralysis. These stages are usually associated with inflammatory responses in the central nervous system (CNS). This study was designed to investigate the effects of C16, an ανβ3 integrin-binding peptide that targets integrins involved in the transendothelial migration of extravasating inflammatory cells. C16 was applied for only 2 weeks, but the benefits of this therapy lasted at least 8 weeks. Multiple histological and immunohistochemical staining studies, western blotting, enzyme-linked immunosorbent assays, electron microscopy, and cortical somatosensory-evoked potential (c-SEP) electrophysiological tests were employed to assess the degree of inflammation, axonal loss, white matter demyelination, neuronal apoptosis, extent of gliosis, expression of pro-inflammatory cytokines, and functional recovery of differently treated EAE model mice. The results showed that C16 treatment inhibited extensive leukocyte and macrophage accumulation and infiltration, reduced the expression of pro-inflammatory cytokines (tumor necrosis factor-α and interferon-γ), and thereby attenuated and delayed the progression of EAE. Moreover, astrogliosis, demyelination, and axonal and neuronal loss were all alleviated in C16-treated EAE animals, contributing to the improvement of function. These data suggest that the C16 peptide may act as a protective agent by reducing neuroinflammatory responses and improving the microenvironment.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • All AH, Walczak P, Agrawal G, Gorelik M, Lee C, Thakor NV, Bulte JW, Kerr DA (2009) Effect of MOG sensitization on somatosensory evoked potential in Lewis rats. J Neurol Sci 284:81–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Arnold SA, Hagg T (2011) Anti-inflammatory treatments during the chronic phase of spinal cord injury improve locomotor function in adult mice. J Neurotrauma 28:1995–2002

    Article  PubMed Central  PubMed  Google Scholar 

  • Balatoni B, Storch MK, Swoboda EM, Schönborn V, Koziel A, Lambrou GN, Hiestand PC, Weissert R, Foster CA (2007) FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 74:307–316

    Article  CAS  PubMed  Google Scholar 

  • Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Bar-Shir A, Engel Y, Gozin M, Weiner HL (2008) Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest 118:1532–1543

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Berard JL, Wolak K, Fournier S, David S (2010) Characterization of relapsing-remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice. Glia 58:434–445

    Article  PubMed  Google Scholar 

  • Bettini M, Rosenthal K, Evavold BD (2009) Pathogenic MOG-reactive CD8+ T cells require MOG-reactive CD4+ T cells for sustained CNS inflammation during chronic EAE. J Neuroimmunol 213:60–68

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR (2014) Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia 62:452–467

    Google Scholar 

  • Cervellini I, Ghezzi P, Mengozzi M (2013) Therapeutic efficacy of erythropoietin in experimental autoimmune encephalomyelitis in mice, a model of multiple sclerosis. Methods Mol Biol 982:163–173

    Article  PubMed  Google Scholar 

  • Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS (1997) Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med 3:73–76

    Article  CAS  PubMed  Google Scholar 

  • Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I (2011) The relevance of animal models in multiple sclerosis research. Pathophysiology 18:21–29

    Article  CAS  PubMed  Google Scholar 

  • Devaux J, Forni C, Beeton C, Barbaria J, Béraud E, Gola M, Crest M (2003) Myelin basic protein-reactive T cells induce conduction failure in vivo but not in vitro. Neuroreport 14:317–320

    Article  CAS  PubMed  Google Scholar 

  • Dore-Duffy P, Wencel M, Katyshev V, Cleary K (2011) Chronic mild hypoxia ameliorates chronic inflammatory activity in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE). Adv Exp Med Biol 701:165–173

    Article  CAS  PubMed  Google Scholar 

  • Fang M, Huang JY, Wang J, Ling SC, Rudd JA, Hu ZY, Xu LH, Yuan ZG, Han S (2011) The anti-neuroinflamatory and neurotrophic effects of combined therapy with Annexin II and Reg-2 on injured spinal cord. Neurosignals 19:16–43

    Article  CAS  PubMed  Google Scholar 

  • Fang M, Sun Y, Hu Z, Yang J, Davies H, Wang B, Ling S, Han S (2013) C16 peptide shown to prevent leukocyte infiltration and alleviate detrimental inflammation in acute allergic encephalomyelitis model. Neuropharmacology 70C:83–99

    Article  Google Scholar 

  • Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 10:942–955

    Article  Google Scholar 

  • Garay L, Gonzalez Deniselle MC, Gierman L, Meyer M, Lima A, Roig P, De Nicola AF (2008) Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 15:76–83

    CAS  PubMed  Google Scholar 

  • Ghezzi P, Mennini T (2001) Tumor necrosis factor and motoneuronal degeneration: an open problem. Neuroimmunomodulation 9:178–182

    Article  CAS  PubMed  Google Scholar 

  • Han S, Arnold SA, Sithu SD, Mahoney ET, Geralds JT, Tran P, Benton RL, Maddie MA, D’Souza SE, Whittemore SR, Hagg T (2010) Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury. Brain 133:1026–1042

    Article  PubMed Central  PubMed  Google Scholar 

  • Hassen GW, Feliberti J, Kesner L, Stracher A, Mokhtarian F (2008) Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res 1236:206–215

    Article  PubMed Central  PubMed  Google Scholar 

  • Kanwar JR, Kanwar RK, Wang D, Krissansen GW (2000) Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression. Immunol Cell Biol 78:641–645

    Article  CAS  PubMed  Google Scholar 

  • Liu XZ, Xu XM, Hu R, Du C, Zhang SX, McDonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395–5406

    CAS  PubMed  Google Scholar 

  • Ma X, Jiang Y, Wu A, Chen X, Pi R, Liu M, Liu Y (2010) Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS One 5:e13489

    Article  PubMed Central  PubMed  Google Scholar 

  • Mangas A, Coveñas R, Bodet D, de León M, Duleu S, Geffard M (2008) Evaluation of the effects of a new drug candidate (GEMSP) in a chronic EAE model. Int J Biol Sci 4:150–160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McGavern DB, Murray PD, Rivera-Quiñones C, Schmelzer JD, Low PA, Rodriguez M (2000) Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 123:519–531

    Article  PubMed  Google Scholar 

  • Mensah-Brown EP, Shahin A, Al Shamisi M, Lukic ML (2011) Early influx of macrophages determines susceptibility to experimental allergic encephalomyelitis in Dark Agouti (DA) rats. J Neuroimmunol 232:68–74

    Article  CAS  PubMed  Google Scholar 

  • Merrill JE, Hanak S, Pu SF, Liang J, Dang C, Iglesias-Bregna D, Harvey B, Zhu B, McMonagle-Strucko K (2009) Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. J Neurol 256:89–103

    Article  CAS  PubMed  Google Scholar 

  • Murugesan N, Paul D, Lemire Y, Shrestha B, Ge S, Pachter JS (2012) Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus. Fluids Barriers CNS 9:15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nair A, Frederick TJ, Miller SD (2008) Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 65:2702–2720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pifarre P, Prado J, Baltrons MA, Giralt M, Gabarro P, Feinstein DL, Hidalgo J, Garcia A (2011) Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. Acta Neuropathol 121:499–508

    Article  CAS  PubMed  Google Scholar 

  • Profyris C, Cheema SS, Zang D, Azari MF, Boyle K, Petratos S (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis 15:415–436

    Article  PubMed  Google Scholar 

  • Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15:1074–1077

    Article  CAS  PubMed  Google Scholar 

  • Roy A, Liu X, Pahan K (2007) Myelin basic protein-primed T cells induce neurotrophins in glial cells via alphavbeta3 integrin. J Biol Chem 282:32222–32232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shu Y, Yang Y, Qiu W, Lu Z, Li Y, Bao J, Feng M, Hu X (2011) Neuroprotection by ulinastatin in experimental autoimmune encephalomyelitis. Neurochem Res 36:1969–1977

    Article  CAS  PubMed  Google Scholar 

  • Slavin A, Ewing C, Liu J, Ichikawa M, Slavin J, Bernard CC (1998) Induction of a multiple sclerosis-like disease in mice with an immunodominantepitope of myelin oligodendrocyte glycoprotein. Autoimmunity 28:109–120

    Article  CAS  PubMed  Google Scholar 

  • Soulika AM, Lee E, McCauley E, Miers L, Bannerman P, Pleasure D (2009) Initiation and progression of axonopathy in experimental autoimmune encephalomyelitis. J Neurosci 29:14965–14979

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tanoue K, Yamashita S, Masuko K, Osaka J, Iai M, Yamada M (2006) Two cases of acute disseminated encephalomyelitis which occurred before the age of 24 months. No To Hattatsu 38:363–367

    PubMed  Google Scholar 

  • Tegla CA, Cudrici C, Rus V, Ito T, Vlaicu S, Singh A, Rus H (2009) Neuroprotective effects of the complement terminal pathway during demyelination: implications for oligodendrocyte survival. J Neuroimmunol 213:3–11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Troncoso E, Muller D, Czellar S, Zoltan Kiss J (2000) Epicranial sensory evoked potential recordings for repeated assessment of cortical functions in mice. J Neurosci Methods 97:51–58

    Article  CAS  PubMed  Google Scholar 

  • Troncoso E, Muller D, Korodi K, Steimer T, Welker E, Kiss JZ (2004) Recovery of evoked potentials, metabolic activity and behavior in a mouse model of somatosensory cortex lesion: role of the neural cell adhesion molecule (NCAM). Cereb Cortex 14:332–341

    Article  CAS  PubMed  Google Scholar 

  • Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, Sofroniew MV (2009) Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 29:11511–11522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Warden P, Bamber NI, Li H, Esposito A, Ahmad KA, Hsu CY, Xu XM (2001) Delayed glial cell death following Wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats. Exp Neurol 168:213–224

    Article  CAS  PubMed  Google Scholar 

  • Weerasinghe D, McHugh KP, Ross FP, Brown EJ, Gisler RH, Imhof BA (1998) A role for the alphavbeta3 integrin in the transmigration of monocytes. J Cell Biol 142:595–607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu J, Drew PD (2007) Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia. J Immunol 178:1904–1913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu J, Chavis JA, Racke MK, Drew PD (2006) Peroxisome proliferator-activated receptor-alpha and retinoid X receptor agonists inhibit inflammatory responses of astrocytes. J Neuroimmunol 176:95–105

    Article  CAS  PubMed  Google Scholar 

  • Yin JX, Tu JL, Lin HJ, Shi FD, Liu RL, Zhao CB, Coons SW, Kuniyoshi S, Shi J (2010) Centrally administered pertussis toxin inhibits microglia migration to the spinal cord and prevents dissemination of disease in an EAE mouse model. PLoS One 5:e12400

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the Zhejiang Provincial Natural Science Foundation of China no. R2110025 and the National Natural Science Foundation of China, project no. 81271333.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Institute of Anatomy and Cell Biology, Medical College, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China

    Fan Zhang, Jing Yang & Shu Han

  2. Department of Electrophysiology, Sir Run Run Shaw Hospital, Medical College, Zhejiang University, Hangzhou, China

    Hong Jiang

Authors
  1. Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shu Han.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1778 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, F., Yang, J., Jiang, H. et al. An ανβ3 Integrin-Binding Peptide Ameliorates Symptoms of Chronic Progressive Experimental Autoimmune Encephalomyelitis by Alleviating Neuroinflammatory Responses in Mice. J Neuroimmune Pharmacol 9, 399–412 (2014). https://doi.org/10.1007/s11481-014-9532-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-014-9532-6

Keywords

Search

Navigation