Subscribe to RSS
DOI: 10.1055/s-0043-105138
Polysialinsäure zur Immunmodulation im Tiermodell der feuchten altersabhängigen Makuladegeneration (AMD)
Polysialic Acid for Immunomodulation in an Animal Model for Wet Age-Related Macular Degeneration (AMD)Publication History
eingereicht 16 January 2017
akzeptiert 03 February 2017
Publication Date:
05 April 2017 (online)
![](https://www.thieme-connect.de/media/klimo/201705/lookinside/thumbnails/10-1055-s-0043-105138_kl1728-1.jpg)
Zusammenfassung
Hintergrund Die chronische Reaktivität des angeborenen Immunsystems zählt zu den pathophysiologisch hoch relevanten Mechanismen bei der Entstehung und Progression der altersabhängigen Makuladegeneration (AMD). Sowohl zelluläre Prozesse, getrieben vor allem durch aktivierte mononukleäre Phagozyten, als auch humorale Immunmechanismen, vermittelt durch ein autoreaktives Komplementsystem, tragen zum degenerativen Geschehen in der Netzhaut bei. Neuste Ergebnisse weisen auf einen direkten Zusammenhang zwischen Immunzellaktivierung, Komplementaktivierung, Schädigung der Bruch-Membran, Fehlfunktion des retinalen Pigmentepithels, Photorezeptordegeneration und choroidaler Neovaskularisierung (CNV) hin. Neben der antiangiogenen Therapie bietet das Immunsystem Ansatzpunkte für komplementäre Therapieoptionen bei der AMD. Der vorliegende Artikel stellt die beispielhafte Anwendung der Polysialinsäure im Mausmodell der feuchten AMD dar.
Material und Methoden Zur Simulation der feuchten AMD wurde das Mausmodell der laserinduzierten CNV verwendet. Polysialinsäure wurde intravitreal appliziert und die Mikrogliaaktivität mittels Iba1-Immunfärbung von Flachpräparaten der Netzhaut und RPE/Aderhaut bestimmt. Gefäßleckage wurde mittels Fluoresceinangiografie bestimmt.
Ergebnisse Die intravitreale Injektion von Polysialinsäure bei der laserinduzierten CNV der Maus führte zu einer verminderten läsionsassoziierten Mikrogliaaktivität sowohl in der Netzhaut als auch dem RPE. Die Gefäßleckage der Laserherde war ebenfalls bei Polysialinsäurebehandlung vermindert.
Schlussfolgerung Die lokale retinale Immunmodulation mittels Polysialinsäure könnte ein vielversprechendes Konzept zur Behandlung der inflammatorischen Komponenten der feuchten AMD darstellen.
Abstract
Background Chronic activation of the innate immune system is a hallmark of retinal degenerative diseases, including age-related macular degeneration (AMD). Overt microglia and macrophage reactivity, as well as dysregulation of the alternative complement system, trigger and sustain retinal degeneration. It is now accepted that there exists a vicious cycle of mononuclear phagocyte reactivity, abnormal intrinsic complement activation, damage of Bruchʼs membrane, dysfunction of the retinal pigment epithelium, photoreceptor degeneration and choroidal neovascularization (CNV). Targeting the innate immune system may, therefore, be a complementary approach to anti-angiogenic therapy. This article presents data from polysialic acid treatment experiments in the laser-induced mouse model of wet AMD.
Material and Methods The laser-CNV mouse model was used to simulate events of neovascular AMD. Polysialic acid was applied by intravitreal injection and microglia activity was assessed with Iba1 staining of retinal and RPE/choroidal flat mounts. Neovascular leakage was determined by fluorescein angiography.
Results Intravitreal injection of polysialic acid reduced retinal and RPE/choroidal lesion-associated microglia activity in the laser-induced mouse model of AMD. Polysialic acid treatment also diminished vascular leakage at laser spots in this model.
Conclusion Local retinal immunomodulation with polysialic acid presents a novel concept for treatment of inflammatory conditions related to neovascular AMD.
-
Literatur
- 1 Augood CA, Vingerling JR, de Jong PT. et al. Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol 2006; 124: 529-535
- 2 Lambert V, Lecomte J, Hansen S. et al. Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. Nat Protoc 2013; 8: 2197-2211
- 3 Hoerster R, Muether PS, Vierkotten S. et al. In-vivo and ex-vivo characterization of laser-induced choroidal neovascularization variability in mice. Graefes Arch Clin Exp Ophthalmol 2012; 250: 1579-1586
- 4 Anderson DH, Radeke MJ, Gallo NB. et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010; 29: 95-112
- 5 Mullins RF, Russell SR, Anderson DH. et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000; 14: 835-846
- 6 Johnson LV, Leitner WP, Staples MK. et al. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 2001; 73: 887-896
- 7 Klein RJ, Zeiss C, Chew EY. et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385-389
- 8 Haines JL, Hauser MA, Schmidt S. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419-421
- 9 Edwards AO, Ritter III R, Abel KJ. et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421-424
- 10 Fritsche LG, Fariss RN, Stambolian D. et al. Age-related macular degeneration: genetics and biology coming together. Annu Rev Genomics Hum Genet 2014; 15: 151-171
- 11 Ersoy L, Ristau T, Hahn M. et al. Genetic and environmental risk factors for age-related macular degeneration in persons 90 years and older. Invest Ophthalmol Vis Sci 2014; 55: 1842-1847
- 12 Bradley DT, Zipfel PF, Hughes AE. Complement in age-related macular degeneration: a focus on function. Eye (Lond) 2011; 25: 683-693
- 13 Fett AL, Hermann MM, Muether PS. et al. Immunohistochemical localization of complement regulatory proteins in the human retina. Histol Histopathol 2012; 27: 357-364
- 14 Schick T, Steinhauer M, Aslanidis A. et al. Local complement activation in aqueous humor in patients with age-related macular degeneration. Eye (Lond) 2017; DOI: 10.1038/eye.2016.328.
- 15 Skerka C, Lauer N, Weinberger AA. et al. Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007; 44: 3398-3406
- 16 Zipfel PF. Complement and immune defense: from innate immunity to human diseases. Immunol Lett 2009; 126: 1-7
- 17 Luo C, Chen M, Xu H. Complement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid. Mol Vis 2011; 17: 1588-1597
- 18 Gupta N, Brown KE, Milam AH. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 2003; 76: 463-471
- 19 Killingsworth MC, Sarks JP, Sarks SH. Macrophages related to Bruchʼs membrane in age-related macular degeneration. Eye (Lond) 1990; 4: 613-621
- 20 Penfold PL, Killingsworth MC, Sarks SH. Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol 1985; 223: 69-76
- 21 Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007; 8: 57-69
- 22 Altay L, Scholz P, Schick T. et al. Association of hyperreflective foci present in early forms of age-related macular degeneration with known age-related macular degeneration risk polymorphisms. Invest Ophthalmol Vis Sci 2016; 57: 4315-4320
- 23 Sierra A, Gottfried-Blackmore AC, McEwen BS. et al. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 2007; 55: 412-424
- 24 Damani MR, Zhao L, Fontainhas AM. et al. Age-related alterations in the dynamic behavior of microglia. Aging Cell 2011; 10: 263-276
- 25 Sene A, Chin-Yee D, Apte RS. Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. Trends Mol Med 2015; 21: 43-51
- 26 Langmann T. Microglia activation in retinal degeneration. J Leukoc Biol 2007; 81: 1345-1351
- 27 Karlstetter M, Scholz R, Rutar M. et al. Retinal microglia: just bystander or target for therapy?. Prog Retin Eye Res 2015; 45: 30-57
- 28 Lückoff A, Caramoy A, Scholz R. et al. Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO Mol Med 2016; 8: 670-678
- 29 Karlstetter M, Kopatz J, Aslanidis A. et al. Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina. EMBO Mol Med 2017; 9: 154-166
- 30 Varki A. Since there are PAMPs and DAMPs, there must be SAMPs? Glycan „self-associated molecular patterns“ dampen innate immunity, but pathogens can mimic them. Glycobiology 2011; 21: 1121-1124
- 31 Jaffe GJ, Ciulla TA, Ciardella AP. et al. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase II b, multicenter, randomized controlled trial. Ophthalmology 2017; 124: 224-234
- 32 Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci 2010; 30: 3482-3488
- 33 Shahraz A, Kopatz J, Mathy R. et al. Anti-inflammatory activity of low molecular weight polysialic acid on human macrophages. Sci Rep 2015; 5: 16800
- 34 Micklisch S, Lin Y, Jacob S. et al. Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. J Neuroinflammation 2017; 14: 4
- 35 Liu J, Copland DA, Horie S. et al. Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice. PloS One 2013; 8: e72935