Project 6 Microglia in AMD

Role of the complement system and microglia in age-related macular degeneration

Summary

Age-related macular degeneration (AMD) is a complex disease leading to vision loss in the elderly. The pathogenesis of AMD is multifactorial and involves several genetic risk factors related to the complement system, a key component of the innate immune system, extracellular matrix biology, and age-related oxidative stress. In situ analyses of post mortem retinas from AMD patients and AMD-like animal models demonstrated reactivity of microglial cells, the resident immune cells of the retina. Our previous work contributed to the identification of risk variants in complement genes in AMD and showed aberrant complement distribution in human AMD retinas. Moreover, we have generated Htra1 transgenic mice, which model pathological changes in Bruch´s membrane, and detected prominent subretinal microglial reactivity. In this project, we first plan to comprehensively characterize the immunological retinal phenotype of Htra1 Tg / Cfh-/- mice, which mirror two key components implicated in AMD. We will study local complement factor expression and distribution, investigate the microglial activity of Htra1 Tg / Cfh-/- mice in situ and ex vivo and study their pro-inflammatory potential by transplantation into healthy retinas. These mouse studies will be complemented by studies in human AMD patients and controls, involving a comparison of systemic versus local ocular complement activation and correlation with malondialdehyde (MDA) as marker for oxidative stress. Moreover, we will evaluate whether hyperreflective dots seen with SD-OCT in neovascular AMD patients are a potential indicator for retinal immune cell reactivity and correlate these findings with complement biomarkers and genetic risk factors. We expect from our studies deeper insight into the role of retinal complement factors and microglia as mediators of chronic inflammation in AMD.

Selected Key Publications of Project 6

Lückoff A, Scholz R, Sennlaub F, Xu H, Langmann T. Comprehensive analysis of mouse retinal mononuclear phagocytes. Nat Protoc. 2017 Jun;12(6):1136-1150.

Schick T, Steinhauer M, Aslanidis A, Altay L, Karlstetter M, Langmann T, Kirschfink M, Fauser S. Local complement activation in aqueous humor in patients  with age-related macular degeneration. Eye (Lond). 2017 May;31(5):810-813.

Karlstetter M, Kopatz J, Aslanidis A, Shahraz A, Caramoy A, Linnartz-Gerlach B, Lin Y, Lückoff A, Fauser S, Düker K, Claude J, Wang Y, Ackermann J, Schmidt T, Hornung V, Skerka C, Langmann T*, Neumann H*. Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina. EMBO Mol Med. 2017 Feb;9(2):154-166.*shared senior authors.

Scholz R, Langmann T. Gut flora connects obesity with pathological angiogenesis in the eye. EMBO Mol Med. 2016 Dec 1;8(12):1361-1363.

Altay L, Scholz P, Schick T, Felsch M, Hoyng CB, den Hollander AI, Langmann T, Fauser S. 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 Aug 1;57(10):4315-20.

Lückoff A, Caramoy A, Scholz R, Prinz M, Kalinke U, Langmann T. Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO Mol Med. 2016 Jun 1;8(6):670-8.

Fritsche LG et al., Ersoy L, Caramoy A, Langmann T et al.,  Fauser S et al., Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016 Feb;48(2):134-43.

Aslanidis A, Karlstetter M, Scholz R, Fauser S, Neumann H, Fried C, Pietsch M, Langmann T. Activated microglia/macrophage whey acidic protein (AMWAP) inhibits NFκB signaling and induces a neuroprotective phenotype in microglia. J Neuroinflammation. 2015 Apr 19;12:77.

Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T. Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res. 2015 Mar;45:30-57.

Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BH, Rupprecht R, Langmann T. Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation 2014 Jan 8;11:3.

More Publications of Project 6

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T. [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klin Monbl Augenheilkd. 2017 May;234(5):679-685.

Langmann T, Fauser S. [Polysialic Acid for Immunomodulation in an Animal Model for Wet Age-Related Macular Degeneration (AMD)]. Klin Monbl Augenheilkd. 2017 May;234(5):657-661.

Martens TF, Peynshaert K, Nascimento TL, Fattal E, Karlstetter M, Langmann T, Picaud S, Demeester J, De Smedt SC, Remaut K, Braeckmans K. Effect of hyaluronic  acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy. Eur J Pharm Sci. 2017 May 30;103:27-35.

Grassmann F, Kiel C, Zimmermann ME, Gorski M, Grassmann V, Stark K; International AMD Genomics Consortium (IAMDGC), Heid IM, Weber BH. Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. Genome Med. 2017 Mar 27;9(1):29.

Nebel C, Aslanidis A, Rashid K, Langmann T. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells. Biochem Biophys Res Commun. 2017 Mar 11;484(3):681-686.

Wolf A, Aslanidis A, Langmann T. Retinal expression and localization of Mef2c support its important role in photoreceptor gene expression. Biochem Biophys Res  Commun. 2017 Jan 29;483(1):346-351.

Micklisch S, Lin Y, Jacob S, Karlstetter M, Dannhausen K, Dasari P, von der Heide M, Dahse HM, Schmölz L, Grassmann F, Alene M, Fauser S, Neumann H, Lorkowski S, Pauly D, Weber BH, Joussen AM, Langmann T, Zipfel PF, Skerka C. Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. J Neuroinflammation. 2017 Jan 5;14(1):4.

Coppieters F, Ascari G, Dannhausen K, Nikopoulos K, Peelman F, Karlstetter M, Xu M, Brachet C, Meunier I, Tsilimbaris MK, Tsika C, Blazaki SV, Vergult S, Farinelli P, Van Laethem T, Bauwens M, De Bruyne M, Chen R, Langmann T, Sui R, Meire F, Rivolta C, Hamel CP, Leroy BP, De Baere E. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. Am J Hum Genet. 2016 Aug 4;99(2):470-80.

Zeilbeck LF, Müller BB, Leopold SA, Senturk B, Langmann T, Tamm ER, Ohlmann A. Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1. Exp Eye Res. 2016 Apr;145:317-26.

Van Schil K, Karlstetter M, Aslanidis A, Dannhausen K, Azam M, Qamar R, Leroy BP, Depasse F, Langmann T, De Baere E. Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7. Sci Rep. 2016 Feb 18;6:21307.

Scholz R, Sobotka M, Caramoy A, Stempfl T, Moehle C, Langmann T. Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration. J Neuroinflammation. 2015 Nov 17;12:209.

Scholz R, Caramoy A, Bhuckory MB, Rashid K, Chen M, Xu H, Grimm C, Langmann T. Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration. J Neuroinflammation. 2015 Nov 2;12:201.

Langmann T. Intracellular Toll-Like Receptors Help Retinal Microglia Sense Corneal Infections. Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7387.

Dannhausen K, Karlstetter M, Caramoy A, Volz C, Jägle H, Liebisch G, Utermöhlen O, Langmann T. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function. Biochem Biophys Res Commun. 2015 Aug 21;464(2):434-40.

Breukink MB, Schellevis RL, Boon CJ, Fauser S, Hoyng CB, den Hollander AI, de Jong EK. Genomic Copy Number Variations of the Complement Component C4B Gene Are Associated With Chronic Central Serous Chorioretinopathy. Invest Ophthalmol Vis Sci. 2015 Aug 1;56(9):5608-13.

Grassmann F, Friedrich U, Fauser S, Schick T, Milenkovic A, Schulz HL, von Strachwitz CN, Bettecken T, Lichtner P, Meitinger T, Arend N, Wolf A, Haritoglou C, Rudolph G, Chakravarthy U, Silvestri G, McKay GJ, Freitag-Wolf S, Krawczak M, Smith RT, Merriam JC, Merriam JE, Allikmets R, Heid IM, Weber BH. A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD). Neuromolecular Med. 2015 Jun;17(2):111-20.

Van Schil K, Meire F, Karlstetter M, Bauwens M, Verdin H, Coppieters F, Scheiffert E, Van Nechel C, Langmann T, Deconinck N, De Baere E. Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion. Genet Med. 2015 Apr;17(4):291-9.

Enders P, Muether PS, Hermann M, Ristau T, Fauser S. Long-term alterations of systemic vascular endothelial growth factor levels in patients treated with ranibizumab for age-related macular degeneration. Retina. 2015 Mar;35(3):454-8.

Szulzewsky F, Pelz A, Feng X, Synowitz M, Markovic D, Langmann T, Holtman IR, Wang X, Eggen BJ, Boddeke HW, Hambardzumyan D, Wolf SA, Kettenmann H. Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PLoS One. 2015 Feb 6;10(2):e0116644.

Langmann T, Ueffing M, Kirchhof B, Holz FG, Pauleikhoff D. [Meeting report — retinal research 2013 in Germany]. Klin Monbl Augenheilkd. 2014 Mar;231(3):266-8.

Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BH, Rupprecht R, Langmann T. Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation. 2014 Jan 8;11:3.

Volz C, Mirza M, Langmann T, Jägle H. Retinal function in aging homozygous Cln3 (?ex7/8) knock-in mice. Adv Exp Med Biol. 2014;801:495-501.
Karlstetter M, Langmann T. Microglia in the aging retina. Adv Exp Med Biol. 2014;801:207-12.

Ristau T, Ersoy L, Lechanteur Y, den Hollander AI, Daha MR, Hahn M, Hoyng CB, Fauser S (2014) Allergy is a protective factor against age-related macular degeneration. Invest Ophthalmol Vis Sci. 55:210-4.

Karlstetter M, Sorusch N, Caramoy A, Dannhausen K, Aslanidis A, Fauser S, Boesl MR, Nagel-Wolfrum K, Tamm ER, Jägle H, Stoehr H, Wolfrum U, Langmann T (2014) Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration. Hum Mol Genet. 23(19):5197-210

Ristau T, Paun C, Ersoy L, Hahn M, Lechanteur Y, Hoyng C, de Jong EK, Daha MR, Kirchhof B, den Hollander AI, Fauser S (2014) Impact of the common genetic associations of age-related macular degeneration upon systemic complement component C3d levels. PLoS One 9(3):e93459.

Helgason H, Sulem P, Duvvari MR, Luo H, Thorleifsson G, Stefansson H, Jonsdottir I, Masson G, Gudbjartsson DF, Walters GB, Magnusson OT, Kong A, Rafnar T, Kiemeney LA, Schoenmaker-Koller FE, Zhao L, Boon CJ, Song Y, Fauser S, Pei M, Ristau T, Patel S, Liakopoulos S, van de Ven JP, Hoyng CB, Ferreyra H, Duan Y, Bernstein PS, Geirsdottir A, Helgadottir G, Stefansson E, den Hollander AI, Zhang K, Jonasson F, Sigurdsson H, Thorsteinsdottir U, Stefansson K (2013) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet. 45:1371-4.

van de Ven JP, Nilsson SC, Tan PL, Buitendijk GH, Ristau T, Mohlin FC, Nabuurs SB, Schoenmaker-Koller FE, Smailhodzic D, Campochiaro PA, Zack DJ, Duvvari MR, Bakker B, Paun CC, Boon CJ, Uitterlinden AG, Liakopoulos S, Klevering BJ, Fauser S, Daha MR, Katsanis N, Klaver CC, Blom AM, Hoyng CB, den Hollander AI (2013) A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet. 45:813-7.

Vierkotten S, Muether PS, Fauser S (2011) Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch’s membrane via cleavage of extracellular matrix components. PLoS One 6:e22959.

Karlstetter M, Walczak Y, Weigelt K, Ebert S, Van den Brulle J, Schwer H, Fuchshofer R, Langmann T (2010) The novel activated microglia/macrophage WAP domain protein, AMWAP, acts as a counter-regulator of proinflammatory response. J Immunol 185:3379-3390.

Langmann T, Di Gioia SA, Rau I, Stohr H, Maksimovic NS, Corbo JC, Renner AB, Zrenner E, Kumaramanickavel G, Karlstetter M, Arsenijevic Y, Weber BH, Gal A, Rivolta C (2010) Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. Am J Hum Genet 87:376-381.

Corbo JC, Lawrence KA, Karlstetter M, Myers CA, Abdelaziz M, Dirkes W, Weigelt K, Seifert M, Benes V, Fritsche LG, Weber BH, Langmann T (2010) CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors. Genome Res 20:1512-1525.