Research progress of microglia in the pathogenesis and treatment of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Jiang Feng ,  Yan Hua

Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China;

Corresponding author：

Yan Hua, Email: phuayan2000@163.com

Keywords：

Microglia; Diabetic retinopathy; Review

DOI：

10.3760/cma.j.issn.1005-1015.2018.04.025

Video：

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Retinal microglial cells are immune cells of the retina and participate in the retinal immune response. In recent years, it has been found that microglia plays an important role in the pathogenesis of diabetic retinopathy (DR), and is involved in the pathological process of neurodegeneration and microvascular disease in DR. Understanding the function of retinal microglial cells and their role in the pathogenesis DR may open up new avenues for the treatment of DR through the precise regulation of microglia

Citation： Jiang Feng, Yan Hua. Research progress of microglia in the pathogenesis and treatment of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2018, 34(4): 412-415. doi: 10.3760/cma.j.issn.1005-1015.2018.04.025 Copy

1.	Stitt AW, Curtis TM, Chen M, et al. The progress in understanding and treatment of diabetic retinopathy[J]. Prog Retin Eye Res, 2016, 51: 156-186.DOI: 10.1016/j.preteyeres.2015.08.001.
2.	Hernández C, Dal Monte M, Simó R, et al. Neuroprotection as a therapeutic target for diabetic retinopathy [J/OL]. J Diabetes Res, 2016, 2016: 9508541[2016-03-31]. http://dx.doi.org/10.1155/2016/9508541. DOI: 10.1155/2016/9508541.
3.	Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic retinopathy[J]. J Neuroinflammation, 2015, 12: 141. DOI: 10.1186/s12974-015-0368-7.
4.	Abcouwer SF. Müller cell-microglia cross talk drives neuroinflammation in diabetic retinopathy[J]. Diabetes, 2017, 66(2): 261-263. DOI: 10.2337/dbi16-0047.
5.	Sorrentino FS, Allkabes M, Salsini G, et al. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy[J]. Life Sci, 2016, 162: 54-59. DOI: 10.1016/j.lfs.2016.08.001.
6.	Arroba AI, Valverde ÁM. Modulation of microglia in the retina: new insights into diabetic retinopathy[J]. Acta Diabetol, 2017, 54(6): 527-533. DOI: 10.1007/s00592-017-0984-z.
7.	Chen L, Yang P, Kijlstra A.Distribution, markers, and functions of retinal microglia[J]. Ocul Immunol Inflamm, 2002, 10(1): 27-39.
8.	Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy[J]. Diabetes Care, 2012, 35(3): 556-564. DOI: 10.2337/dc11-1909.
9.	Karlstetter M, Scholz R, Rutar M, et al. Retinal microglia: just bystander or target for therapy? [J]. Prog Retin Eye Res, 2015, 45: 30-57. DOI: 10.1016/j.preteyeres.2014.11.004.
10.	Crotti A, Ransohoff RM. Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling[J]. Immunity, 2016, 44(3): 505-515. DOI: 10.1016/j.immuni.2016.02.013.
11.	Li L, Eter N, Heiduschka P. The microglia in healthy and diseased retina[J]. Exp Eye Res, 2015, 136: 116-130. DOI: 10.1016/j.exer.2015.04.020.
12.	Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms[J]. Nat Rev Neurosci, 2007, 8(1): 57-69. DOI: 10.1038/nrn2038.
13.	Kaur C, Rathnasamy G, Ling EA. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina[J]. J Neuroimmune Pharmacol, 2013, 8(1): 66-78. DOI: 10.1007/s11481-012-9347-2.
14.	Jin N, Gao L, Fan X, et al. Friend or foe? Resident microglia vs bone marrow-derived microglia and their roles in the retinal degeneration[J]. Mol Neurobiol, 2017, 54(6): 4094-4112. DOI: 10.1007/s12035-016-9960-9.
15.	Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease[J]. Nat Rev Immunol, 2011, 11(11): 775-787. DOI: 10.1038/nri3086.
16.	Yun JH, Park SW, Kim KJ, et al. Endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins: implications for diabetic retinopathy[J]. J Cell Physiol, 2017, 232(5): 1123-1134. DOI: 10.1002/jcp.25575.
17.	Ding X, Zhang M, Gu R, et al. Activated microglia induce the production of reactive oxygen species and promote apoptosis of co-cultured retinal microvascular pericytes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2017, 255(4): 777-788. DOI: 10.1007/s00417-016-3578-5.
18.	Arroba AI, Alcalde-Estevez E, García-Ramírez M, et al. Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice[J]. Biochim Biophys Acta, 2016, 1862(9): 1663-1674. DOI: 10.1016/j.bbadis.2016.05.024.
19.	Grigsby JG, Cardona SM, Pouw CE, et al. The role of microglia in diabetic retinopathy [J/OL]. J Ophthalmol, 2014, 2014: 705783[2014-08-31]. http://dx.doi.org/10.1155/2014/705783. DOI: 10.1155/2014/705783.
20.	Rungger-Brandle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2000, 41(7): 1971-1980.
21.	Zeng XX, Ng YK, Ling EA. Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats[J]. Vis Neurosci, 2000, 17(3): 463-471.
22.	Omri S, Behar-Cohen F, de Kozak Y, et al. Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCzeta in the Goto Kakizaki rat model[J]. Am J Pathol, 2011, 179(2): 942-953. DOI: 10.1016/j.ajpath.2011.04.018.
23.	Chen X, Zhou H, Gong Y, et al.Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2015, 253(4): 519-525. DOI: 10.1007/s00417-014-2727-y.
24.	Zeng HY, Green WR, Tso MO. Microglial activation in human diabetic retinopathy[J]. Arch Ophthalmol, 2008, 126(2): 227-232. DOI: 10.1001/archophthalmol.2007.65.
25.	Vujosevic S, Bini S, Midena G, et al. Hyperreflective intraretinal spots in diabetics without and with nonproliferative diabetic retinopathy: an in vivo study using spectral domain OCT [J/OL]. J Diabetes Res, 2013, 2013: 491835[2013-12-09].http://dx.doi.org/10.1155/2013/491835. DOI: 10.1155/2013/491835.
26.	van Dijk HW, Kok PH, Garvin M, et al. Selective loss of inner retinal layer thickness in type 1 diabetic patients with minimal diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2009, 50(7): 3404-3409. DOI: 10.1167/iovs.08-3143.
27.	van Dijk HW, Verbraak FD, Kok PH, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes[J]. Invest Ophthalmol Vis Sci, 2010; 51(7): 3660-3665. DOI: 10.1167/iovs.09-5041.
28.	van Dijk HW, Verbraak FD, Kok PH, et al. Early neurodegeneration in the retina of type 2 diabetic patients[J]. Invest Ophthalmol Vis Sci, 2012; 53(6): 2715-2719. DOI: 10.1167/iovs.11-8997.
29.	Tang J, Kern TS. Inflammation in diabetic retinopathy[J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
30.	Wong A, Dukic-Stefanovic S, Gasic-Milenkovic J, et al. Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia[J]. Prog Retin Eye Res, 2001, 14(12): 1961-1967.
31.	Wang AL, Yu AC, He QH, et al. AGEs mediated expression and secretion of TNF alpha in rat retinal microglia[J]. Exp Eye Res, 2007, 84(5): 905-913.DOI: 10.1016/j.exer.2007.01.011.
32.	Swaroop S, Sengupta N, Suryawanshi AR, et al. HSP60 plays a regulatory role in IL-1beta-induced microglial inflammation via TLR4-p38 MAPK axis[J]. J Neuroinflammation, 2016, 13: 27. DOI: 10.1186/s12974-016-0486-x.
33.	Tuo J, Smith BC, Bojanowski CM, et al. The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration[J]. FASEB J, 2004, 18(11): 1297-1299. DOI: 10.1096/fj.04-1862fje.
34.	Cardona SM, Mendiola AS, Yang YC, et al.Disruption of fractalkine signaling leads to microglial activation and neuronal damage in the diabetic retina[J]. ASN Neuro, 2015, 7(5): 1759091415608204[2015-10-29]. http://journals.sagepub.com/doi/pdf/10.1177/1759091415608204.DOI: 10.1177/1759091415608204.
35.	Mendiola AS, Garza R, Cardona SM, et al. Fractalkine signaling attenuates perivascular clustering of microglia and fibrinogen leakage during systemic inflammation in mouse models of diabetic retinopathy[J]. Front Cell Neurosci, 2016, 10: 303. DOI: 10.3389/fncel.2016.00303.
36.	Krady JK, Basu A, Allen CM, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy[J]. Diabetes, 2005, 54(5): 1559-1565.
37.	Glybina IV, Kennedy A, Ashton P, et al. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats[J]. Invest Ophthalmol Vis Sci, 2010, 51(8): 4243-4252. DOI: 10.1167/iovs.09-4492.
38.	Singhal S, Lawrence JM, Salt TE, et al. Triamcinolone attenuates macrophage/microglia accumulation associated with NMDA-induced RGC death and facilitates survival of Muller stem cell grafts[J]. Exp Eye Res, 2010, 90(2): 308-315. DOI: 10.1016/j.exer.2009.11.008.
39.	Shen W, Lee SR, Araujo J, et al. Effect of glucocorticoids on neuronal and vascular pathology in a transgenic model of selective Müller cell ablation.Glia, 2014, 62(7): 1110-1124. DOI: 10.1002/glia.22666.
40.	Couturier A, Bousquet E, Zhao M, et al. Anti-vascular endothelial growth factor acts on retinal microglia/macrophage activation in a rat model of ocular inflammation[J]. Mol Vis, 2014, 20: 908-920.
41.	Roche SL, Wyse-Jackson AC, Gomez-Vicente V, et al. Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-CX3CR1 signaling [J/OL]. PLoS One, 2016, 11(11): 0165197[2016-11-04]. https://doi.org/10.1371/journal.pone.0165197. DOI: 10.1371/journal.pone.0165197.

1. Stitt AW, Curtis TM, Chen M, et al. The progress in understanding and treatment of diabetic retinopathy[J]. Prog Retin Eye Res, 2016, 51: 156-186.DOI: 10.1016/j.preteyeres.2015.08.001.
2. Hernández C, Dal Monte M, Simó R, et al. Neuroprotection as a therapeutic target for diabetic retinopathy [J/OL]. J Diabetes Res, 2016, 2016: 9508541[2016-03-31]. http://dx.doi.org/10.1155/2016/9508541. DOI: 10.1155/2016/9508541.
3. Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic retinopathy[J]. J Neuroinflammation, 2015, 12: 141. DOI: 10.1186/s12974-015-0368-7.
4. Abcouwer SF. Müller cell-microglia cross talk drives neuroinflammation in diabetic retinopathy[J]. Diabetes, 2017, 66(2): 261-263. DOI: 10.2337/dbi16-0047.
5. Sorrentino FS, Allkabes M, Salsini G, et al. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy[J]. Life Sci, 2016, 162: 54-59. DOI: 10.1016/j.lfs.2016.08.001.
6. Arroba AI, Valverde ÁM. Modulation of microglia in the retina: new insights into diabetic retinopathy[J]. Acta Diabetol, 2017, 54(6): 527-533. DOI: 10.1007/s00592-017-0984-z.
7. Chen L, Yang P, Kijlstra A.Distribution, markers, and functions of retinal microglia[J]. Ocul Immunol Inflamm, 2002, 10(1): 27-39.
8. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy[J]. Diabetes Care, 2012, 35(3): 556-564. DOI: 10.2337/dc11-1909.
9. Karlstetter M, Scholz R, Rutar M, et al. Retinal microglia: just bystander or target for therapy? [J]. Prog Retin Eye Res, 2015, 45: 30-57. DOI: 10.1016/j.preteyeres.2014.11.004.
10. Crotti A, Ransohoff RM. Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling[J]. Immunity, 2016, 44(3): 505-515. DOI: 10.1016/j.immuni.2016.02.013.
11. Li L, Eter N, Heiduschka P. The microglia in healthy and diseased retina[J]. Exp Eye Res, 2015, 136: 116-130. DOI: 10.1016/j.exer.2015.04.020.
12. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms[J]. Nat Rev Neurosci, 2007, 8(1): 57-69. DOI: 10.1038/nrn2038.
13. Kaur C, Rathnasamy G, Ling EA. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina[J]. J Neuroimmune Pharmacol, 2013, 8(1): 66-78. DOI: 10.1007/s11481-012-9347-2.
14. Jin N, Gao L, Fan X, et al. Friend or foe? Resident microglia vs bone marrow-derived microglia and their roles in the retinal degeneration[J]. Mol Neurobiol, 2017, 54(6): 4094-4112. DOI: 10.1007/s12035-016-9960-9.
15. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease[J]. Nat Rev Immunol, 2011, 11(11): 775-787. DOI: 10.1038/nri3086.
16. Yun JH, Park SW, Kim KJ, et al. Endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins: implications for diabetic retinopathy[J]. J Cell Physiol, 2017, 232(5): 1123-1134. DOI: 10.1002/jcp.25575.
17. Ding X, Zhang M, Gu R, et al. Activated microglia induce the production of reactive oxygen species and promote apoptosis of co-cultured retinal microvascular pericytes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2017, 255(4): 777-788. DOI: 10.1007/s00417-016-3578-5.
18. Arroba AI, Alcalde-Estevez E, García-Ramírez M, et al. Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice[J]. Biochim Biophys Acta, 2016, 1862(9): 1663-1674. DOI: 10.1016/j.bbadis.2016.05.024.
19. Grigsby JG, Cardona SM, Pouw CE, et al. The role of microglia in diabetic retinopathy [J/OL]. J Ophthalmol, 2014, 2014: 705783[2014-08-31]. http://dx.doi.org/10.1155/2014/705783. DOI: 10.1155/2014/705783.
20. Rungger-Brandle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2000, 41(7): 1971-1980.
21. Zeng XX, Ng YK, Ling EA. Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats[J]. Vis Neurosci, 2000, 17(3): 463-471.
22. Omri S, Behar-Cohen F, de Kozak Y, et al. Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCzeta in the Goto Kakizaki rat model[J]. Am J Pathol, 2011, 179(2): 942-953. DOI: 10.1016/j.ajpath.2011.04.018.
23. Chen X, Zhou H, Gong Y, et al.Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes[J]. Graefe’s Arch Clin Exp Ophthalmol, 2015, 253(4): 519-525. DOI: 10.1007/s00417-014-2727-y.
24. Zeng HY, Green WR, Tso MO. Microglial activation in human diabetic retinopathy[J]. Arch Ophthalmol, 2008, 126(2): 227-232. DOI: 10.1001/archophthalmol.2007.65.
25. Vujosevic S, Bini S, Midena G, et al. Hyperreflective intraretinal spots in diabetics without and with nonproliferative diabetic retinopathy: an in vivo study using spectral domain OCT [J/OL]. J Diabetes Res, 2013, 2013: 491835[2013-12-09].http://dx.doi.org/10.1155/2013/491835. DOI: 10.1155/2013/491835.
26. van Dijk HW, Kok PH, Garvin M, et al. Selective loss of inner retinal layer thickness in type 1 diabetic patients with minimal diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2009, 50(7): 3404-3409. DOI: 10.1167/iovs.08-3143.
27. van Dijk HW, Verbraak FD, Kok PH, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes[J]. Invest Ophthalmol Vis Sci, 2010; 51(7): 3660-3665. DOI: 10.1167/iovs.09-5041.
28. van Dijk HW, Verbraak FD, Kok PH, et al. Early neurodegeneration in the retina of type 2 diabetic patients[J]. Invest Ophthalmol Vis Sci, 2012; 53(6): 2715-2719. DOI: 10.1167/iovs.11-8997.
29. Tang J, Kern TS. Inflammation in diabetic retinopathy[J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
30. Wong A, Dukic-Stefanovic S, Gasic-Milenkovic J, et al. Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia[J]. Prog Retin Eye Res, 2001, 14(12): 1961-1967.
31. Wang AL, Yu AC, He QH, et al. AGEs mediated expression and secretion of TNF alpha in rat retinal microglia[J]. Exp Eye Res, 2007, 84(5): 905-913.DOI: 10.1016/j.exer.2007.01.011.
32. Swaroop S, Sengupta N, Suryawanshi AR, et al. HSP60 plays a regulatory role in IL-1beta-induced microglial inflammation via TLR4-p38 MAPK axis[J]. J Neuroinflammation, 2016, 13: 27. DOI: 10.1186/s12974-016-0486-x.
33. Tuo J, Smith BC, Bojanowski CM, et al. The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration[J]. FASEB J, 2004, 18(11): 1297-1299. DOI: 10.1096/fj.04-1862fje.
34. Cardona SM, Mendiola AS, Yang YC, et al.Disruption of fractalkine signaling leads to microglial activation and neuronal damage in the diabetic retina[J]. ASN Neuro, 2015, 7(5): 1759091415608204[2015-10-29]. http://journals.sagepub.com/doi/pdf/10.1177/1759091415608204.DOI: 10.1177/1759091415608204.
35. Mendiola AS, Garza R, Cardona SM, et al. Fractalkine signaling attenuates perivascular clustering of microglia and fibrinogen leakage during systemic inflammation in mouse models of diabetic retinopathy[J]. Front Cell Neurosci, 2016, 10: 303. DOI: 10.3389/fncel.2016.00303.
36. Krady JK, Basu A, Allen CM, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy[J]. Diabetes, 2005, 54(5): 1559-1565.
37. Glybina IV, Kennedy A, Ashton P, et al. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats[J]. Invest Ophthalmol Vis Sci, 2010, 51(8): 4243-4252. DOI: 10.1167/iovs.09-4492.
38. Singhal S, Lawrence JM, Salt TE, et al. Triamcinolone attenuates macrophage/microglia accumulation associated with NMDA-induced RGC death and facilitates survival of Muller stem cell grafts[J]. Exp Eye Res, 2010, 90(2): 308-315. DOI: 10.1016/j.exer.2009.11.008.
39. Shen W, Lee SR, Araujo J, et al. Effect of glucocorticoids on neuronal and vascular pathology in a transgenic model of selective Müller cell ablation.Glia, 2014, 62(7): 1110-1124. DOI: 10.1002/glia.22666.
40. Couturier A, Bousquet E, Zhao M, et al. Anti-vascular endothelial growth factor acts on retinal microglia/macrophage activation in a rat model of ocular inflammation[J]. Mol Vis, 2014, 20: 908-920.
41. Roche SL, Wyse-Jackson AC, Gomez-Vicente V, et al. Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-CX3CR1 signaling [J/OL]. PLoS One, 2016, 11(11): 0165197[2016-11-04]. https://doi.org/10.1371/journal.pone.0165197. DOI: 10.1371/journal.pone.0165197.

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