[en] Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up.
Disciplines :
Ophthalmology
Author, co-author :
LAMBERT, Vincent ✱; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
hansen, Sylvain ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Schoumacher, Matthieu ✱; Université de Liège - ULiège > Cancer-Tumours and development biology
Lecomte, Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Leenders, Justine
Hubert, Pascale ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Herfs, Michael ; Université de Liège - ULiège > Cancer-Experimental Pathology
Blacher, Silvia ; Université de Liège - ULiège > Cancer-Tumours and development biology
Carnet, Oriane; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Yip, Cassandre ; Université de Liège - ULiège > Cancer-Tumours and development biology
BLAISE, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
DUCHATEAU, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
LOCHT, Bénédicte ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
THYS, Michèle ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
CAVALIER, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Service de chimie clinique
GOTHOT, André ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Service d'hématologie biologique et immuno-hématologie
Govaerts, Bernadette; Université Catholique de Louvain - UCL > Institute of statistics biostatistics and actuarial sciences
RAKIC, Jean-Marie ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ophtalmologie
Noël, Agnès ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
De Tullio, Pascal ✱; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] ULiège FSR - Université de Liège. Fonds spéciaux pour la recherche [BE] Fondation Léon Fredericq [BE] DGTRE - Région wallonne. Direction générale des Technologies, de la Recherche et de l'Énergie [BE] FEDER - Fonds Européen de Développement Régional [BE]
Colijn JM, Buitendijk GHS, Prokofyeva E, Alves D, Cachulo ML, Khawaja AP, Cougnard-Gregoire A, Merle BMJ, Korb C, Erke MG, Bron A, Anastasopoulos E, Meester-Smoor MA, Segato T, Piermarocchi S, de Jong PTVM, Vingerling JR, Topouzis F, Creuzot-Garcher C, Bertelsen G, Pfeiffer N, Fletcher AE, Foster PJ, Silva R, Korobelnik J-F, Delcourt C, Klaver CCW, EYE-RISK consortium, European Eye Epidemiology (E3) consortium (2017) Prevalence of age-related macular degeneration in Europe: the past and the future. Ophthalmology 124:1753–1763
Schmidt-Erfurth U, Klimscha S, Waldstein SM, Bogunović H (2017) A view of the current and future role of optical coherence tomography in the management of age-related macular degeneration. Eye (Lond) 31:26–44
Lai T-T, Hsieh Y-T, Yang C-M, Ho T-C, Yang C-H (2019) Biomarkers of optical coherence tomography in evaluating the treatment outcomes of neovascular age-related macular degeneration: a real-world study. Sci Rep 9. 10.1038/s41598-018-36704-6,
Cascella R, Strafella C, Caputo V, Errichiello V, Zampatti S, Milano F, Potenza S, Mauriello S, Novelli G, Ricci F, Cusumano A, Giardina E (2018) Towards the application of precision medicine in age-related macular degeneration. Prog Retin Eye Res 63:132–146
DeAngelis MM, Owen LA, Morrison MA, Morgan DJ, Li M, Shakoor A, Vitale A, Iyengar S, Stambolian D, Kim IK, Farrer LA (2017) Genetics of age-related macular degeneration (AMD). Hum Mol Genet 26:R45–R50
Liu K, Chen LJ, Lai TY, Tam PO, Ho M, Chiang SW, Liu DT, Young AL, Yang Z, Pang CP (2014) Genes in the high-density lipoprotein metabolic pathway in age-related macular degeneration and polypoidal choroidal vasculopathy. Ophthalmology 121:911–916
Nita M, Grzybowski A, Ascaso FJ, Huerva V (2014) Age-related macular degeneration in the aspect of chronic low-grade inflammation (pathophysiological parainflammation). Mediat Inflamm 2014:930671–930610
Lavalette S, Raoul W, Houssier M, Camelo S, Levy O, Calippe B, Jonet L, Behar-Cohen F, Chemtob S, Guillonneau X, Combadiere C, Sennlaub F (2011) Interleukin-1beta inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am J Pathol 178:2416–2423
Doyle SL, Ozaki E, Brennan K, Humphries MM, Mulfaul K, Keaney J, Kenna PF, Maminishkis A, Kiang AS, Saunders SP, Hams E, Lavelle EC, Gardiner C, Fallon PG, Adamson P, Humphries P, Campbell M (2014) IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Sci Transl Med 6:230ra44
Xi H, Katschke KJ Jr, Li Y, Truong T, Lee WP, Diehl L, Rangell L, Tao J, Arceo R, Eastham-Anderson J, Hackney JA, Iglesias A, Cote-Sierra J, Elstrott J, Weimer RM, Campagne MV (2016) IL-33 amplifies an innate immune response in the degenerating retina. J Exp Med 213:189–207
Colijn JM, den Hollander AI, Demirkan A, Cougnard-Grégoire A, Verzijden T, Kersten E, Meester-Smoor MA, Merle BMJ, Papageorgiou G, Ahmad S, Mulder MT, Costa MA, Benlian P, Bertelsen G, Bron AM, Claes B, Creuzot-Garcher C, Erke MG, Fauser S, Foster PJ, Hammond CJ, Hense H-W, Hoyng CB, Khawaja AP, Korobelnik J-F, Piermarocchi S, Segato T, Silva R, Souied EH, Williams KM, van Duijn CM, Delcourt C, Klaver CCW, Acar N, Altay L, Anastosopoulos E, Azuara-Blanco A, Berendschot T, Berendschot T, Bergen A, Bertelsen G, Binquet C, Bird A, Bobak M, Larsen MB, Boon C, Bourne R, Brétillon L, Broe R, Bron A, Buitendijk G, Cachulo ML, Capuano V, Carrière I, Chakravarthy U, Chan M, Chang P, Colijn J, Cougnard-Grégoire A, Cree A, Creuzot-Garcher C, Cumberland P, Cunha-Vaz J, Daien V, De Jong E, Deak G, Delcourt C, Delyfer M-N, den Hollander A, Dietzel M, Erke MG, Faria P, Farinha C, Fauser S, Finger R, Fletcher A, Foster P, Founti P, Gorgels T, Grauslund J, Grus F, Hammond C, Heesterbeek T, Hense H-W, Hermann M, Hoehn R, Hogg R, Holz F, Hoyng C, Jansonius N, Janssen S, de Jong E, Khawaja A, Klaver C, Korobelnik J-F, Lamparter J, Le Goff M, Lehtimäki T, Leung I, Lotery A, Mauschitz M, Meester M, Merle B, Meyer zu Westrup V, Midena E, Miotto S, Mirshahi A, Mohan-Saïd S, Mueller M, Muldrew A, Murta J, Nickels S, Nunes S, Owen C, Peto T, Pfeiffer N, Piermarocchi S, Prokofyeva E, Rahi J, Raitakari O, Rauscher F, Ribeiro L, Rougier M-B, Rudnicka A, Sahel J, Salonikiou A, Sanchez C, Schick T, Schmitz-Valckenberg S, Schuster A, Schweitzer C, Segato T, Shehata J, Silva R, Silvestri G, Simader C, Souied E, Speckauskas M, Springelkamp H, Tapp R, Topouzis F, van Leeuwen E, Verhoeven V, Verzijden T, Vingerling H, Von Hanno T, Williams K, Wolfram C, Yip J, Zerbib J, Ajana S, Arango-Gonzalez B, Arndt V, Bhatia V, Bhattacharya SS, Biarnés M, Borrell A, Bühren S, Calado SM, Colijn JM, Cougnard-Grégoire A, Dammeier S, de Jong EK, De la Cerda B, Delcourt C, den Hollander AI, Diaz-Corrales FJ, Diether S, Emri E, Endermann T, Ferraro LL, Garcia M, Heesterbeek TJ, Honisch S, Hoyng CB, Kersten E, Kilger E, CCW K, Langen H, Lengyel I, Luthert P, Maugeais C, Meester-Smoor M, BMJ MI, Monés J, Nogoceke E, Peto T, Pool FM, Rodríguez E, Ueffing M, Ulrich Bartz-Schmidt KU, van Leeuwen EM, Verzijden T, Zumbansen M (2019) Increased high-density lipoprotein levels associated with age-related macular degeneration. Ophthalmology 126:393–406
Noel A, Jost M, Lambert V, Lecomte J, Rakic JM (2007) Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts. Trends Mol Med 13:345–352
Cheung GCM, Lai TYY, Gomi F, Ruamviboonsuk P, Koh A, Lee WK (2017) Anti-VEGF therapy for neovascular AMD and polypoidal choroidal vasculopathy. Asia Pac J Ophthalmol (Phila) 6:527–534
Nagai N, Suzuki M, Uchida A, Kurihara T, Kamoshita M, Minami S, Shinoda H, Tsubota K, Ozawa Y (2016) Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment. Sci Rep 6:29619
Sun X, Yang S, Zhao J (2016) Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. DDDT 1857. 10.2147/DDDT.S97653
Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, Eldem B, Mones J, Richard G, Bandello F (2014) Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol 98:1144–1167
Frédérich M, Pirotte B, Fillet M, de Tullio P (2016) Metabolomics as a challenging approach for medicinal chemistry and personalized medicine. J Med Chem 59:8649–8666
Beger RD, Dunn W, Schmidt MA, Gross SS, Kirwan JA, Cascante M, Brennan L, Wishart DS, Oresic M, Hankemeier T, Broadhurst DI, Lane AN, Suhre K, Kastenmüller G, Sumner SJ, Thiele I, Fiehn O, Kaddurah-Daouk R, for “Precision Medicine and Pharmacometabolomics Task Group”-Metabolomics Society Initiative (2016) Metabolomics enables precision medicine: “a white paper, community perspective”. Metabolomics 12:149
Li B, He X, Jia W, Li H (2017) Novel applications of metabolomics in personalized medicine: a mini-review. Molecules 22. 10.3390/molecules22071173
Draoui N, de Zeeuw P, Carmeliet P (2017) Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism. Open Biol 7:170219
Mills E, O’Neill LAJ (2014) Succinate: a metabolic signal in inflammation. Trends Cell Biol 24:313–320
Brown CN, Green BD, Thompson RB, den Hollander AI, Lengyel I (2019) Metabolomics and age-related macular degeneration. Metabolites 9. 10.3390/metabo9010004
Luo D, Deng T, Yuan W, Deng H, Jin M (2017) Plasma metabolomic study in Chinese patients with wet age-related macular degeneration. BMC Ophthalmol 17:165
Mitchell SL, Uppal K, Williamson SM, Liu K, Burgess LG, Tran V, Umfress AC, Jarrell KL, Cooke Bailey JN, Agarwal A, Pericak-Vance M, Haines JL, Scott WK, Jones DP, Brantley MA (2018) The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 59:4978–4985
Osborn MP, Park Y, Parks MB, Burgess LG, Uppal K, Lee K, Jones DP, Brantley MA Jr (2013) Metabolome-wide association study of neovascular age-related macular degeneration. PLoS One 8:e72737
Laíns I, Duarte D, Barros AS, Martins AS, Gil J, Miller JB, Marques M, Mesquita T, Kim IK, Cachulo M d L, Vavvas D, Carreira IM, Murta JN, Silva R, Miller JW, Husain D, Gil AM (2017) Human plasma metabolomics in age-related macular degeneration (AMD) using nuclear magnetic resonance spectroscopy. PLoS One 12:e0177749
Lambert V, Lecomte J, Hansen S, Blacher S, Gonzalez ML, Struman I, Sounni NE, Rozet E, de Tullio P, Foidart JM, Rakic JM, Noel A (2013) Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. Nat Protoc 8:2197–2211
Adeva M, González-Lucán M, Seco M, Donapetry C (2013) Enzymes involved in l-lactate metabolism in humans. Mitochondrion 13:615–629
Roche TE, Hiromasa Y (2007) Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 64:830–849
Bian L, Josefsson E, Jonsson IM, Verdrengh M, Ohlsson C, Bokarewa M, Tarkowski A, Magnusson M (2009) Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice. Arthritis Res Ther 11:R132
Matheus N, Hansen S, Rozet E, Peixoto P, Maquoi E, Lambert V, Noel A, Frederich M, Mottet D, de Tullio P (2014) An easy, convenient cell and tissue extraction protocol for nuclear magnetic resonance metabolomics. Phytochem Anal: PCA 25:342–349
Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De Tullio P, Mari B, De Pauw E, Noel A (2014) Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab 20:280–294
Mia S, Warnecke A, Zhang X-M, Malmström V, Harris RA (2014) An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF- β yields a dominant immunosuppressive phenotype. Scand J Immunol 79:305–314
Edin S, Wikberg ML, Rutegård J, Oldenborg P-A, Palmqvist R (2013) Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells. PLoS One 8:e74982. 10.1371/journal.pone.0074982 DOI: 10.1371/journal.pone.0074982
Hubert P, van den Brûle F, Giannini SL, Franzen-Detrooz E, Boniver J, Delvenne P (1999) Colonization of in vitro-formed cervical human papillomavirus-associated (pre)neoplastic lesions with dendritic cells. Am J Pathol 154:775–784
Pennesi ME, Neuringer M, Courtney RJ (2012) Animal models of age related macular degeneration. Mol Asp Med 33:487–509
Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994
Kersten E, Paun CC, Schellevis RL, Hoyng CB, Delcourt C, Lengyel I, Peto T, Ueffing M, Klaver CCW, Dammeier S, den Hollander AI, de Jong EK (2018) Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration. Surv Ophthalmol 63:9–39
Porporato PE, Payen VL, De Saedeleer CJ, Préat V, Thissen J-P, Feron O, Sonveaux P (2012) Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15:581–592
Skeie JM, Mullins RF (2009) Macrophages in neovascular age-related macular degeneration: friends or foes? Eye (Lond) 23:747–755
Sakurai E, Anand A, Ambati BK, van Rooijen N, Ambati J (2003) Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3578–3585
Zandi S, Nakao S, Chun KH, Fiorina P, Sun D, Arita R, Zhao M, Kim E, Schueller O, Campbell S, Taher M, Melhorn MI, Schering A, Gatti F, Tezza S, Xie F, Vergani A, Yoshida S, Ishikawa K, Yamaguchi M, Sasaki F, Schmidt-Ullrich R, Hata Y, Enaida H, Yuzawa M, Yokomizo T, Kim YB, Sweetnam P, Ishibashi T, Hafezi-Moghadam A (2015) ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep 10:1173–1186
Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MPJ, Donners MMPC (2014) Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17:109–118
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563
Dhup S, Dadhich RK, Porporato PE, Sonveaux P (2012) Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 18:1319–1330
Hurley JB, Lindsay KJ, Du J (2015) Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res 93:1079–1092
De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G, Phng LK, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins RT, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven PP, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis RJ, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P (2013) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:651–663
Parmeggiani F, Romano MR, Costagliola C, Semeraro F, Incorvaia C, D’Angelo S, Perri P, De Palma P, De Nadai K, Sebastiani A (2012) Mechanism of inflammation in age-related macular degeneration. Mediat Inflamm 2012:546786–546716
Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001) Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 51:349–353
Quennet V, Yaromina A, Zips D, Rosner A, Walenta S, Baumann M, Mueller-Klieser W (2006) Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice. Radiother Oncol 81:130–135
