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Komplementaktivierung nach Induktion einer okulären Hypertension im Tiermodell

Complement activation after induction of ocular hypertension in an animal model

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Zusammenfassung

Hintergrund und Fragestellung

Neben dem erhöhten Augeninnendruck (IOD) als Hauptrisikofaktor gibt es Hinweise auf eine mögliche Beteiligung des Immunsystems beim Glaukom. Unsere Studie untersucht, ob bereits ein moderater IOD-Anstieg zu einer Aktivierung des Komplementsystems führt.

Methode

In den linken Augen der Ratten wurde der IOD experimentell erhöht, während das jeweils rechte Auge als Kontrolle diente. Der IOD wurde regelmäßig gemessen. Die Anzahl retinaler Ganglienzellen (RGZ) wurde mittels NeuN-Färbung detektiert. Eine mögliche Aktivierung des Komplementsystems wurde anhand der Marker C3, Membranangriffskomplex (MAC) und Mannose-bindendes Lektin (MBL) untersucht. Weitere Untersuchungen zielten auf mögliche Veränderungen der Gliazellen [saures Gliafaserprotein (GFAP) und Vimentin] und der Apoptoserate (Bax) ab.

Ergebnisse

Elf Tage nach Injektion kam es zu einem moderaten IOD-Anstieg in der OHT-Gruppe. Dieser blieb bis zum Ende der Studie erhöht (28 Tage: p = 0,0005). In der OHT-Gruppe zeigte sich eine signifikante Abnahme der RGZ (p = 0,02). Zusätzlich konnte eine vermehrte Aktivierung der Komplementfaktoren C3 und MAC sowohl in der Ganglienzellschicht (C3: p = 0,001; MAC: p = 0,02) als auch in der gesamten Retina (C3: p = 0,002; MAC: p = 0,012) ermittelt werden. Eine Aktivierung über den Lektinweg durch MBL konnte nicht gezeigt werden (p = 0,40). Ebenso kam es zu diesem Zeitpunkt zu keiner Aktivierung der Gliazellen (GFAP: p = 0,97, Vimentin: p = 0,99) oder zu einer vermehrten Apoptoserate via des Bax-Signalwegs (p = 0,90).

Schlussfolgerung

Die Ergebnisse legen nahe, dass das Komplementsystem auch bei einem moderaten IOD-Anstieg am Ganglienzellverlust beteiligt ist. Darauf weist das Auftreten von C3 und MAC in der OHT-Gruppe hin.

Abstract

Background

Although an elevated intraocular pressure (IOP) is known as the main risk factor for glaucoma, many studies also showed an involvement of the immune system in this disease. In this study we investigated if a moderate increase in IOP leads to activation of the complement system.

Methods

The IOP was elevated experimentally in the left eye of rats, whereas the fellow eye served as the control. The IOP was measured at regular intervals. The number of retinal ganglion cells (RGC) was quantified via NeuN staining. To evaluate the activation of the complement system staining for C3, membrane attack complex (MAC), and mannose-binding lectin (MBL) was performed. Furthermore, we investigated possible glia activation (GFAP and vimentin) and apoptosis (Bax).

Results

A moderate elevation of the IOP was noted from day 11 after induction of ocular hypertension (OHT) until the end of the study (28 days, p = 0.0005). In the OHT-group significantly fewer RGCs (p = 0.02) were detected. Additionally, we noted significant C3 and MAC activation in the ganglion cell layer (C3, p = 0.001 and MAC, p = 0.02) as well as in the total retina (C3, p = 0.002 and MAC, p = 0.012). An activation via the lectin pathway by MBL staining could not be detected (p = 0.40). At this point in time no alterations with regard to glia cells were noted (GFAP, p = 0.97 and vimentin, p = 0.99). No apoptosis via Bax pathway could be observed (p = 0.90).

Conclusion

The results suggest that the complement system is involved in the loss of RGCs even by a moderate IOP elevation which was indicated by significantly more C3 and MAC depositions in the OHT group.

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Literatur

  1. Almasieh M, Wilson AM, Morquette B et al (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181

    Article  CAS  PubMed  Google Scholar 

  2. Coleman AL, Miglior S (2008) Risk factors for glaucoma onset and progression. Surv Ophthalmol 53(Suppl1):S3–S10

    Article  PubMed  Google Scholar 

  3. European Glaucoma Society (2014) Terminology and guidelines for glaucoma, 3. Aufl.

  4. Feng L, Chen H, Suyeoka G et al (2013) A laser-induced mouse model of chronic ocular hypertension to characterize visual defects. J Vis Exp 78

  5. Guo Y, Johnson E, Cepurna W et al (2009) Does elevated intraocular pressure reduce retinal TRKB-mediated survival signaling in experimental glaucoma? Exp Eye Res 89:921–933

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Hernandez M, Rodriguez FD, Sharma SC et al (2009) Immunohistochemical changes in rat retinas at various time periods of elevated intraocular pressure. Mol Vis 15:2696–2709

    PubMed Central  PubMed  Google Scholar 

  7. Horstmann L, Schmid H, Heinen AP et al (2013) Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of anexperimental autoimmune encephalomyelitis model. J Neuroinflammation 10:120

    Article  PubMed Central  PubMed  Google Scholar 

  8. Huang W, Dobberfuhl A, Filippopoulos T et al (2005) Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma. Am J Pathol 167:673–681

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Jha P, Banda H, Tytarenko R et al (2011) Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma. Mol Immunol 48:2151–2158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Joachim SC, Grus FH, Kraft D et al (2009) Complex antibody profile changes in an experimental autoimmune glaucoma animal model. Invest Ophthalmol Vis Sci 50:4734–4742

    Article  PubMed  Google Scholar 

  11. Joachim SC, Mondon C, Gramlich OW et al (2014) Apoptotic retinal ganglion cell death in an autoimmune glaucoma model is accompanied by antibody depositions. J Mol Neurosci 52:216–224

    Article  CAS  PubMed  Google Scholar 

  12. Joachim SC, Reinehr S, Kuehn S et al (2013) Immune response against ocular tissues after immunization with optic nerve antigens in a model of autoimmune glaucoma. Mol Vis 19:1804–1814

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Johnson TV, Tomarev SI (2010) Rodent models of glaucoma. Brain Res Bull 81:349–358

    Article  PubMed Central  PubMed  Google Scholar 

  14. Kuehn MH, Kim CY, Ostojic J et al (2006) Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res 83:620–628

    Article  CAS  PubMed  Google Scholar 

  15. Li Y, Schlamp CL, Poulsen KP et al (2000) Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli. Exp Eye Res 71:209–213

    Article  CAS  PubMed  Google Scholar 

  16. Lingor P, Koeberle P, Kugler S et al (2005) Down-regulation of apoptosis mediators by RNAi inhibits axotomy-induced retinal ganglion cell death in vivo. Brain 128:550–558

    Article  PubMed  Google Scholar 

  17. Morrison JC, Jia L, Cepurna W et al (2009) Reliability and sensitivity of the TonoLab rebound tonometer in awake Brown Norway rats. Invest Ophthalmol Vis Sci 50:2802–2808

    Article  PubMed Central  PubMed  Google Scholar 

  18. Morrison JC, Johnson E, Cepurna WO (2008) Rat models for glaucoma research. Prog Brain Res 173:285–301

    Article  PubMed  Google Scholar 

  19. Morrison JC, Moore CG, Deppmeier LM et al (1997) A rat model of chronic pressure-induced optic nerve damage. Exp Eye Res 64:85–96

    Article  CAS  PubMed  Google Scholar 

  20. Naskar R, Wissing M, Thanos S (2002) Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Invest Ophthalmol Vis Sci 43:2962–2968

    PubMed  Google Scholar 

  21. Nickells RW, Semaan SJ, Schlamp CL (2008) Involvement of the Bcl2 gene family in the signaling and control of retinal ganglion cell death. Prog Brain Res 173:423–435

    Article  CAS  PubMed  Google Scholar 

  22. Pease ME, Cone FE, Gelman S et al (2011) Calibration of the TonoLab tonometer in mice with spontaneous or experimental glaucoma. Invest Ophthalmol Vis Sci 52:858–864

    Article  PubMed Central  PubMed  Google Scholar 

  23. Qin Q, Patil K, Sharma SC (2004) The role of Bax-inhibiting peptide in retinal ganglion cell apoptosis after optic nerve transection. Neurosci Lett 372:17–21

    Article  CAS  PubMed  Google Scholar 

  24. Qu J, Wang D, Grosskreutz CL (2010) Mechanisms of retinal ganglion cell injury and defense in glaucoma. Exp Eye Res 91:48–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ramirez AI, Salazar JJ, De Hoz R et al (2010) Quantification of the effect of different levels of IOP in the astroglia of the rat retina ipsilateral and contralateral to experimental glaucoma. Invest Ophthalmol Vis Sci 51:5690–5696

    Article  PubMed  Google Scholar 

  27. Sappington RM, Carlson BJ, Crish SD et al (2010) The microbead occlusion model: a paradigm for induced ocular hypertension in rats and mice. Invest Ophthalmol Vis Sci 51:207–216

    Article  PubMed Central  PubMed  Google Scholar 

  28. Tezel G (2011) The immune response in glaucoma: a perspective on the roles of oxidative stress. Exp Eye Res 93:178–186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Verardo MR, Lewis GP, Takeda M et al (2008) Abnormal reactivity of muller cells after retinal detachment in mice deficient in GFAP and vimentin. Invest Ophthalmol Vis Sci 49:3659–3665

    Article  PubMed Central  PubMed  Google Scholar 

  30. Wang X, Tay SS, Ng YK (2000) An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res 132:476–484

    Article  CAS  PubMed  Google Scholar 

  31. Zhong L (2013) A modified chronic ocular hypertension rat model for retinal ganglion cell neuroprotection. Front Med 7:367–377

    Article  PubMed  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. S. Becker, S. Reinehr, H.B. Dick und S.C. Joachim geben an, dass kein Interessenkonflikt besteht. Alle nationalen Richtlinien zur Haltung und zum Umgang mit Labortieren wurden eingehalten und die notwendigen Zustimmungen der zuständigen Behörden liegen vor.

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Authors and Affiliations

  1. Experimental Eye Research Institute, Universitäts-Augenklinik, Ruhr-Universität Bochum, In der Schornau 23–25, 44892, Bochum, Deutschland

    S. Becker, S. Reinehr, H. Burkhard Dick &  S.C. Joachim

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  1. S. Becker
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  2. S. Reinehr
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  3. H. Burkhard Dick
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  4. S.C. Joachim
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Corresponding author

Correspondence to S.C. Joachim.

Additional information

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Sebastian Becker und Sabrina Reinehr: Diese beiden Autoren veröffentlichen gleichberechtigt.

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Förderung: Deutsche Forschungsgemeinschaft (DFG) JO-886/1-1, FoRUM (Ruhr-Universität Bochum).

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Becker, S., Reinehr, S., Burkhard Dick, H. et al. Komplementaktivierung nach Induktion einer okulären Hypertension im Tiermodell. Ophthalmologe 112, 41–48 (2015). https://doi.org/10.1007/s00347-014-3100-6

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