Abstract
Age-related macular degeneration (AMD) is the leading cause of legal blindness and visual impairment in individuals over 60 years of age in the Western World. A common morphological denominator in all forms of AMD is the accumulation of microglia within the sub-retinal space, which is believed to be a contributing factor to AMD progression. However, the signaling pathway and molecular players regulating microglial recruitment have not been completely identified. Multiple in-vitro and in-vivo studies, to date, have highlighted the contributions of nuclear receptor ligands in the treatment of inflammation related disorders such as atherosclerosis and Alzheimer’s disease. Given that inflammation and the immune response play a vital role in the initiation and progression of AMD, in this brief review we will highlight some of these studies with a particular focus on the lipid activated “adopted orphan” nuclear receptors, the liver x receptors (LXRs) and the peroxisome proliferator-activated receptors (PPARs). The results of these studies strongly support the rationale that treatment with LXR and PPAR ligands may ameliorate microglial activation in the sub-retinal space and ultimately slow down or reverse the progression of AMD.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Apfel R, Benbrook D, Lernhardt E et al (1994) A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 14:7025–7035
Berger J, Moller DE (2002) The mechanisms of action of PPARs. Ann Rev Med 53:409–435
Castrillo A, Tontonoz P (2004) Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Ann Rev Cell Dev Biol 20:455–480
Chawla A, Barak Y, Nagy L et al (2001a) PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nature Med 7:48–52
Chawla A, Boisvert WA, Lee CH et al (2001b) A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171
Coleman HR, Chan CC, Ferris FL, 3rd et al (2008) Age-related macular degeneration. Lancet 372:1835–1845
Combadiere C, Feumi C, Raoul W et al (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117:2920–2928
Cui G, Qin X, Wu L et al (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 121:658–670
Dreyer C, Krey G, Keller H et al (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887
Escher P, Braissant O, Basu-Modak S et al (2001) Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142:4195–4202
Grygiel-Gorniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review. Nutrition J 13:17
Gupta N, Brown KE, Milam AH (2003) Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76:463–471
Hindinger C, Hinton DR, Kirwin SJ et al (2006) Liver X receptor activation decreases the severity of experimental autoimmune encephalomyelitis. J Neurosci Res 84:1225–1234
Holtkamp GM, Kijlstra A, Peek R et al (2001) Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Ret Eye Res 20:29–48
Jakobsson T, Treuter E, Gustafsson JA et al (2012) Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Trend Pharm Sci 33:394–404
Karlstetter M, Langmann T (2014) Microglia in the aging retina. Adv Exp Med Biol 801:207–212
Kliewer SA, Forman BM, Blumberg B et al (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359
Laffitte BA, Repa JJ, Joseph SB et al (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98:507–512
Lehmann JM, Kliewer SA, Moore LB et al (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140
Liu Y, Qiu de K, Ma X (2012) Liver X receptors bridge hepatic lipid metabolism and inflammation. J Digest Dis 13:69–74
Ng TF, Streilein JW (2001) Light-induced migration of retinal microglia into the subretinal space. Invest Ophthalmol Vis Sci 42:3301–3310
Patel M, Chan CC (2008) Immunopathological aspects of age-related macular degeneration. Semin Immunopathol 30:97–110
Rigamonti E, Chinetti-Gbaguidi G, Staels B (2008) Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterio Thromb Vasc Biol 28:1050–1059
Schnegg CI, Robbins ME (2011) Neuroprotective mechanisms of PPARdelta: modulation of oxidative stress and inflammatory processes. PPAR Res 2011:373560
Schupp M, Lazar MA (2010) Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem 285:40409–40415
Sene A, Khan AA, Cox D et al (2013) Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab 17:549–561
Streilein JW, Ma N, Wenkel H et al (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 42:487–495
Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156
Tuo J, Bojanowski CM, Zhou M et al (2007) Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest Ophthalmol Vis Sci 48:3827–3836
Viennois E, Pommier AJ, Mouzat K et al (2011) Targeting liver X receptors in human health: deadlock or promising trail? Expert Opin Ther Targets 15:219–232
Wang YY, Dahle MK, Steffensen KR et al (2009) Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages. Shock 32:548–553
Zamiri P, Sugita S, Streilein JW (2007) Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chem Immunol Allergy 92:86–93
Zhang-Gandhi CX, Drew PD (2007) Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes. J Neuroimmun 183:50–59
Acknowledgements
Many thanks to the funding agencies supporting our research endeavors: The International Retinal Research Foundation Loris and David Rich Post-doctoral Fellowship (MC), NEI EY02868 (GM), P30 EY05722, and a Research to Prevent Blindness, Inc. Sybil B. Harrington Scholar award (GM).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this paper
Cite this paper
Choudhary, M., Malek, G. (2016). A Brief Discussion on Lipid Activated Nuclear Receptors and their Potential Role in Regulating Microglia in Age-Related Macular Degeneration (AMD). In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-17121-0_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-17120-3
Online ISBN: 978-3-319-17121-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)