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Modulation of microglia in the retina: new insights into diabetic retinopathy

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Abstract

During last decades, the diagnosis of diabetes has been associated with several chronic complications such as diabetic retinopathy (DR). Recent studies of DR have revealed an inflammatory component, which precedes the detection of alterations in the visual function. During DR, the inflammatory process presents two opposite roles depending on the polarization of resident immune cells of the retina triggering proinflammatory (M1) or antiinflammatory (M2) actions. In an early stage of DR, the M2 response concurs with the M1 and is able to ameliorate inflammation and delay the progression of the disease. However, during the progression of DR, the M1 response is maintained whereas the M2 declines and, in this scenario, the classical proinflammatory signaling pathways are chronically activated leading to retinal neurodegeneration and the loss of visual function. The M1/M2 responses are closely related to the activation and polarization of microglial cells. This review aims to offer an overview of the recent insights into the role of microglial cells during inflammation in DR. We have focused on the possibility of modulating microglia polarization as a new therapeutic strategy in DR treatments.

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References

  1. Bourne RR et al (2013) Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health 1(6):e339–e349

    Article  PubMed  Google Scholar 

  2. Romero-Aroca P et al (2016) Changes observed in diabetic retinopathy: eight-year follow-up of a Spanish population. Br J Ophthalmol 100(10):1366–1371

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cheung N, Mitchell P, Wong TY (2010) Diabetic retinopathy. Lancet 376(9735):124–136

    Article  PubMed  Google Scholar 

  4. Nentwich MM, Ulbig MW (2015) Diabetic retinopathy—ocular complications of diabetes mellitus. World J Diabetes 6(3):489–499

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oellers P, Mahmoud TH (2016) Surgery for proliferative diabetic retinopathy: new tips and tricks. J Ophthalmic Vis Res 11(1):93–99

    Article  PubMed  PubMed Central  Google Scholar 

  6. Porta M, Bandello F (2002) Diabetic retinopathy A clinical update. Diabetologia 45(12):1617–1634

    Article  CAS  PubMed  Google Scholar 

  7. Aiello LP, D.E.R. Group (2014) Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 37(1):17–23

    Article  CAS  PubMed  Google Scholar 

  8. Antonetti DA, Klein R, Gardner TW (2012) Diabetic retinopathy. N Engl J Med 366(13):1227–1239

    Article  CAS  PubMed  Google Scholar 

  9. van Dijk HW et al (2012) Early neurodegeneration in the retina of type 2 diabetic patients. Invest Ophthalmol Vis Sci 53(6):2715–2719

    Article  PubMed  PubMed Central  Google Scholar 

  10. Simo R, Hernandez C, European R (2014) Consortium for the early treatment of diabetic, neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab 25(1):23–33

    Article  CAS  PubMed  Google Scholar 

  11. Crosby-Nwaobi R et al (2015) cross talk between lipid metabolism and inflammatory markers in patients with diabetic retinopathy. J Diabetes Res 2015:191382

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kowluru RA, Mishra M (2015) Contribution of epigenetics in diabetic retinopathy. Sci China Life Sci 58(6):556–563

    Article  CAS  PubMed  Google Scholar 

  13. Gardner TW et al (2011) An integrated approach to diabetic retinopathy research. Arch Ophthalmol 129(2):230–235

    Article  PubMed  PubMed Central  Google Scholar 

  14. Anand-Apte B et al (2010) Betacellulin induces increased retinal vascular permeability in mice. PLoS ONE 5(10):e13444

    Article  PubMed  PubMed Central  Google Scholar 

  15. Powell ED, Field RA (1964) Diabetic retinopathy and rheumatoid arthritis. Lancet 2(7349):17–18

    Article  CAS  PubMed  Google Scholar 

  16. Brucklacher RM et al (2008) Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response. BMC Med Genomics 1:26

    Article  PubMed  PubMed Central  Google Scholar 

  17. Joussen AM et al (2001) Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 158(1):147–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Joussen AM et al (2004) A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 18(12):1450–1452

    CAS  PubMed  Google Scholar 

  19. Silva PS, Sun JK, Aiello LP (2009) Role of steroids in the management of diabetic macular edema and proliferative diabetic retinopathy. Semin Ophthalmol 24(2):93–99

    Article  PubMed  Google Scholar 

  20. Vujosevic S et al (2016) Proteome analysis of retinal glia cells-related inflammatory cytokines in the aqueous humour of diabetic patients. Acta Ophthalmol 94(1):56–64

    Article  CAS  PubMed  Google Scholar 

  21. Kettenmann H et al (2011) Physiology of microglia. Physiol Rev 91(2):461–553

    Article  CAS  PubMed  Google Scholar 

  22. Davalos D et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758

    Article  CAS  PubMed  Google Scholar 

  23. Lynch MA (2009) The multifaceted profile of activated microglia. Mol Neurobiol 40(2):139–156

    Article  CAS  PubMed  Google Scholar 

  24. Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158(1):15–24

    Article  CAS  PubMed  Google Scholar 

  25. Arroba AI et al (2016) Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice. Biochim Biophys Acta 1862(9):1663–1674

    Article  CAS  PubMed  Google Scholar 

  26. Su F et al (2015) Fluoxetine and S-citalopram inhibit M1 activation and promote M2 activation of microglia in vitro. Neuroscience 294:60–68

    Article  CAS  PubMed  Google Scholar 

  27. Lampron A, Elali A, Rivest S (2013) Innate immunity in the CNS: redefining the relationship between the CNS and Its environment. Neuron 78(2):214–232

    Article  CAS  PubMed  Google Scholar 

  28. Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  CAS  PubMed  Google Scholar 

  29. Ajami B et al (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14(9):1142–1149

    Article  CAS  PubMed  Google Scholar 

  30. Higuchi M et al (2011) Alzheimer’s disease and microglia. Rinsho Shinkeigaku 51(11):1031

    Article  PubMed  Google Scholar 

  31. Ouchi Y et al (2005) Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 57(2):168–175

    Article  CAS  PubMed  Google Scholar 

  32. Bosco A et al (2015) Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis Model Mech 8(5):443–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vujosevic S et al (2013) Hyperreflective intraretinal spots in diabetics without and with nonproliferative diabetic retinopathy: an in vivo study using spectral domain OCT. J Diabetes Res 2013:491835

    PubMed  PubMed Central  Google Scholar 

  34. Robinson R et al (2012) Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech 5(4):444–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bogdanov P et al (2014) The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration. PLoS ONE 9(5):e97302

    Article  PubMed  PubMed Central  Google Scholar 

  36. Holopigian K et al (1992) A comparison of photopic and scotopic electroretinographic changes in early diabetic retinopathy. Invest Ophthalmol Vis Sci 33(10):2773–2780

    CAS  PubMed  Google Scholar 

  37. Shirao Y, Kawasaki K (1998) Electrical responses from diabetic retina. Prog Retin Eye Res 17(1):59–76

    Article  CAS  PubMed  Google Scholar 

  38. Kinoshita J et al (2015) Sildenafil-induced reversible impairment of rod and cone phototransduction in monkeys. Invest Ophthalmol Vis Sci 56(1):664–673

    Article  CAS  PubMed  Google Scholar 

  39. Kline RP, Ripps H, Dowling JE (1978) Generation of b-wave currents in the skate retina. Proc Natl Acad Sci USA 75(11):5727–5731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Klemp K et al (2005) The multifocal ERG in diabetic patients without retinopathy during euglycemic clamping. Invest Ophthalmol Vis Sci 46(7):2620–2626

    Article  PubMed  Google Scholar 

  41. Kahn SE et al (2006) Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes 55(8):2357–2364

    Article  CAS  PubMed  Google Scholar 

  42. Kim CS et al (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30(9):1347–1355

    Article  CAS  Google Scholar 

  43. Bruewer M et al (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 171(11):6164–6172

    Article  CAS  PubMed  Google Scholar 

  44. Brun P et al (2007) Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 292(2):G518–G525

    Article  CAS  PubMed  Google Scholar 

  45. Wada T et al (2013) Cilostazol ameliorates systemic insulin resistance in diabetic db/db mice by suppressing chronic inflammation in adipose tissue via modulation of both adipocyte and macrophage functions. Eur J Pharmacol 707(1–3):120–129

    Article  CAS  PubMed  Google Scholar 

  46. Hotamisligil GS, Erbay E (2008) Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8(12):923–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu Y et al (2015) Decreased expression levels of Nurr1 are associated with chronic inflammation in patients with type 2 diabetes. Mol Med Rep 12(4):5487–5493

    CAS  PubMed  Google Scholar 

  48. Dong N et al (2014) Retinal neuronal MCP-1 induced by AGEs stimulates TNF-alpha expression in rat microglia via p38, ERK, and NF-kappaB pathways. Mol Vis 20:616–628

    PubMed  PubMed Central  Google Scholar 

  49. Legacy J et al (2013) Granulocyte macrophage colony-stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin-dependent mechanism. J Neurosci Res 91(6):771–779

    Article  CAS  PubMed  Google Scholar 

  50. Sappington RM, Chan M, Calkins DJ (2006) Interleukin-6 protects retinal ganglion cells from pressure-induced death. Invest Ophthalmol Vis Sci 47(7):2932–2942

    Article  PubMed  Google Scholar 

  51. Li Q et al (2002) Early retinal damage in experimental diabetes: electroretinographical and morphological observations. Exp Eye Res 74(5):615–625

    Article  CAS  PubMed  Google Scholar 

  52. Engerman RL, Kern TS (1995) Retinopathy in animal models of diabetes. Diabetes Metab Rev 11(2):109–120

    Article  CAS  PubMed  Google Scholar 

  53. Obrosova IG et al (2003) Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 52(3):864–871

    Article  CAS  PubMed  Google Scholar 

  54. Kato N et al (2003) Long-term treatment with fidarestat suppresses the development of diabetic retinopathy in STZ-induced diabetic rats. J Diabetes Complications 17(6):374–379

    Article  PubMed  Google Scholar 

  55. Hernandez C et al (2016) Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes 65(1):172–187

    CAS  PubMed  Google Scholar 

  56. Park KW et al (2007) Interleukin-10 endogenously expressed in microglia prevents lipopolysaccharide-induced neurodegeneration in the rat cerebral cortex in vivo. Exp Mol Med 39(6):812–819

    Article  CAS  PubMed  Google Scholar 

  57. Du L et al (2016) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol. doi:10.1007/s12035-016-0245-0

    Google Scholar 

  58. Jiao H et al (2015) Spatiotemporal cadence of macrophage polarisation in a model of light-induced retinal degeneration. PLoS ONE 10(12):e0143952

    Article  PubMed  PubMed Central  Google Scholar 

  59. Arroba AI et al (2011) Microglia-mediated IGF-I neuroprotection in the rd10 mouse model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 52(12):9124–9130

    Article  PubMed  Google Scholar 

  60. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69

    Article  CAS  PubMed  Google Scholar 

  61. O’Koren EG, Mathew R, Saban DR (2016) Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci Rep 6:20636

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wang Y et al (2012) Autoantibody against transient receptor potential M1 cation channels of retinal ON bipolar cells in paraneoplastic vitelliform retinopathy. BMC Ophthalmol 12:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cai Y et al (2016) Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation 13(1):53

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mittal K, Katare DP (2016) Shared links between type 2 diabetes mellitus and Alzheimer’s disease: a review. Diabetes Metab Syndr 10(2 Suppl 1):S144–S149

    Article  PubMed  Google Scholar 

  65. Verdile G et al (2015) Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease. Mediators Inflamm 2015:105828

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lim JK et al (2016) The eye as a biomarker for Alzheimer’s disease. Front Neurosci 10:536

    Article  PubMed  PubMed Central  Google Scholar 

  67. Reed BT, Behar-Cohen F, Krantic S (2016) Seeing early signs of Alzheimer’s disease through the lens of the eye. Curr Alzheimer Res 14(1):6–17

    Article  Google Scholar 

  68. Serini S, Calviello G (2016) Reduction of oxidative/nitrosative stress in brain and its involvement in the neuroprotective effect of n-3 PUFA in Alzheimer’s disease. Curr Alzheimer Res 13(2):123–134

    Article  CAS  PubMed  Google Scholar 

  69. Roche SL et al (2016) Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-CX3CR1 signaling. PLoS ONE 11(11):e0165197

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The research of A.M.V. laboratory has been supported by the Spanish Ministry of Economy and Competitivity (Grant SAF2015-65267-R MINECO/FEDER cofounded by the Fondos Europeos de Desarrollo Regional de la Unión Europea), Instituto de Salud Carlos III (Grant INFLAMES-PIE14/00045 and CIBERdem), and European Union (FP7 HEALTH.2011.2.4.3.1, EUROCONDOR Grant Agreement Number 278040). We acknowledge all EUROCONDOR partners for support and helpful discussions.

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Correspondence to Ana I. Arroba or Ángela M. Valverde.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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All animal procedures were performed according to the Ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Arroba, A.I., Valverde, Á.M. Modulation of microglia in the retina: new insights into diabetic retinopathy. Acta Diabetol 54, 527–533 (2017). https://doi.org/10.1007/s00592-017-0984-z

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