Advertisement

Cell and Tissue Research

, Volume 374, Issue 1, pp 25–38 | Cite as

Microglial density determines the appearance of pathological neovascular tufts in oxygen-induced retinopathy

  • Wenqin Xu
  • Zhicha Hu
  • Yang Lv
  • Guorui Dou
  • Zifeng Zhang
  • Haiyan Wang
  • Yusheng Wang
Regular Article

Abstract

The oxygen-induced retinopathy (OIR) animal model established in C57 mice and SD rats has been widely used in retinal neovascular disease studies, while Balb/c mice have not been used because Balb/c OIR mice lack neovascular tufts. One study found a substantial difference in the density of retinal microglia between C57 and Balb/c mice; however, no direct evidence could clarify whether the density of retinal microglia in Balb/c mice led to this difference. In our study, intraperitoneal injection of minocycline was used to inhibit the activation of microglia and intravitreal injection of clodronate liposomes was used to decrease the density of microglia in Balb/c OIR model mice. We found that with the decline in microglia induced by the two drugs, the avascular area in treated Balb/c OIR mice was higher than that in untreated Balb/c OIR mice; moreover, a small area of neovascular tufts appeared at P17. After checking the expression of Iba1, a microglial marker and GFAP, an astrocyte and Müller cell marker, we found that minocycline and clodronate could inhibit the activation of microglia or decrease the density of microglia, while they had no significant effect on astrocytes and Müller cells. Therefore, these data suggest that the density of microglia in the retina may determine the result of vasculopathy in OIR mice to some extent. In future studies, predicting the development of retinal neovascular diseases by detecting the density of microglia in living animals or human beings with newly developed instruments and methods may be useful.

Keywords

Microglia Retinal neovascularization Oxygen-induced retinopathy Minocycline Clodronate liposomes 

Notes

Acknowledgements

The study was supported by grants from the National Natural Science Foundation of China (81470655, 81570856, 81770936).

Author contributions

WQX: conducted experiments, analysed data, wrote the manuscript. ZCH, YL: reviewed the manuscript. GRD, HYW, ZFZ and CMG: provided experimental supervision and helpful discussions. Y.S.W. made critical revisions and approved the final version. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Ashwell KW, Hollander H, Streit W, Stone J (1989) The appearance and distribution of microglia in the developing retina of the rat. Vis Neurosci 2:437–448CrossRefPubMedGoogle Scholar
  2. Bian M, Du X, Cui J, Wang P, Wang W, Zhu W, Zhang T, Chen Y (2016) Celastrol protects mouse retinas from bright light-induced degeneration through inhibition of oxidative stress and inflammation. J Neuroinflammation 13:50CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bodeutsch N, Thanos S (2000) Migration of phagocytotic cells and development of the murine intraretinal microglial network: an in vivo study using fluorescent dyes. Glia 32:91–101CrossRefPubMedGoogle Scholar
  4. Brandenburg S, Muller A, Turkowski K, Radev YT, Rot S, Schmidt C, Bungert AD, Acker G, Schorr A, Hippe A, Miller K, Heppner FL, Homey B, Vajkoczy P (2016) Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol 131:365–378CrossRefPubMedGoogle Scholar
  5. Bucher F, Stahl A, Agostini HT, Martin G (2013) Hyperoxia causes reduced density of retinal astrocytes in the central avascular zone in the mouse model of oxygen-induced retinopathy. Mol Cell Neurosci 56:225–233CrossRefPubMedGoogle Scholar
  6. Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S (2006) Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 47:3595–3602CrossRefPubMedGoogle Scholar
  7. Clemens V, Hellmann-Regen J, Regen F (2016) Minocycline-mediated decrease of TNF-alpha synthesis and indoleamine 2,3-dioxygenase expression in activated primary human microglia-like cells is retinoid-dependent. Eur Neuropsychopharmacol 262:S266–S267CrossRefGoogle Scholar
  8. Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem NJ, Serhan CN, Smith L (2007) Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 13:868–873CrossRefPubMedPubMedCentralGoogle Scholar
  9. Diaz-Araya CM, Provis JM, Penfold PL, Billson FA (1995) Development of microglial topography in human retina. J Comp Neurol 363:53–68CrossRefPubMedGoogle Scholar
  10. Dorrell MI, Aguilar E, Jacobson R, Trauger SA, Friedlander J, Siuzdak G, Friedlander M (2010) Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy. Glia 58:43–54CrossRefPubMedPubMedCentralGoogle Scholar
  11. Fischer F, Martin G, Agostini HT (2011) Activation of retinal microglia rather than microglial cell density correlates with retinal neovascularization in the mouse model of oxygen-induced retinopathy. J Neuroinflammation 8:120CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gao X, Wang Y, Li X, Hou H, Su J, Yao L, Zhang J (2016) Macrophages promote vasculogenesis of retinal neovascularization in an oxygen-induced retinopathy model in mice. Cell Tissue Res 364:599–610CrossRefPubMedGoogle Scholar
  13. Gariano RF, Gardner TW (2005) Retinal angiogenesis in development and disease. Nature 438:960–966CrossRefPubMedPubMedCentralGoogle Scholar
  14. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845CrossRefPubMedPubMedCentralGoogle Scholar
  15. Gottschall PE, Deb S (1996) Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. Neuroimmunodulat 3:69–75CrossRefGoogle Scholar
  16. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155CrossRefPubMedGoogle Scholar
  17. Hartnett ME, Penn JS (2013) Mechanisms and management of retinopathy of prematurity. N Engl J Med 368:1162–1163PubMedGoogle Scholar
  18. Hellstrom A, Smith LE, Dammann O (2013) Retinopathy of prematurity. Lancet 382:1445–1457CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hunt S (2007) Increased dietary intake of omega-3-PUFA reduces pathological retinal angiogenesis. Ophthalmology 104:727–729CrossRefGoogle Scholar
  20. Jiang Y, Wang H, Culp D, Yang Z, Fotheringham L, Flannery J, Hammond S, Kafri T, Hartnett ME (2014) Targeting Muller cell-derived VEGF164 to reduce intravitreal neovascularization in the rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 55:824–831CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kataoka K, Nishiguchi KM, Kaneko H, van Rooijen N, Kachi S, Terasaki H (2011) The roles of Vitreal macrophages and circulating leukocytes in retinal neovascularization. Invest Ophthalmol Vis Sci 52:1431–1438CrossRefPubMedGoogle Scholar
  22. Li R, Yang X, Wang Y, Chu Z, Liu T, Zhu T, Gao X, Ma Z (2013) Effect(s) of preterm birth on normal retinal vascular development and oxygen-induced retinopathy in the neonatal rat. Curr Eye Res 38:1266–1273CrossRefPubMedGoogle Scholar
  23. Liu X, Mashour GA, Webster HF, Kurtz A (1998) Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. Glia 24:390–397CrossRefPubMedGoogle Scholar
  24. Liu X, Chu T, Su H, Guo A, Wu W (2014) Neural progenitor cell apoptosis and differentiation were affected by activated microglia in spinal cord slice culture. Neurol Sci 35:415–419CrossRefPubMedGoogle Scholar
  25. Lu YZ, Lin CH, Cheng FC, Hsueh CM (2005) Molecular mechanisms responsible for microglia-derived protection of Sprague-Dawley rat brain cells during in vitro ischemia. Neurocsi Lett 373:159–164CrossRefGoogle Scholar
  26. Mitra RN, Merwin MJ, Han Z, Conley SM, Al-Ubaidi MR, Naash MI (2014) Yttrium oxide nanoparticles prevent photoreceptor death in a light-damage model of retinal degeneration. Free Radical Bio Med 75:140–148CrossRefGoogle Scholar
  27. Nelson LH, Lenz KM (2017) Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats. Behav Brain Res 316:279–293CrossRefPubMedGoogle Scholar
  28. Nishida A, Takahashi M, Tanihara H, Nakano I, Takahashi JB, Mizoguchi A, Ide C, Honda Y (2000) Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina. Invest Ophthalmol Vis Sci 41:4268–4274PubMedGoogle Scholar
  29. Penn JS, Tolman BL, Henry MM (1994) Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 35:3429–3435PubMedGoogle Scholar
  30. Portillo JC, Lopez CY, Miao Y, Tang J, Sheibani N, Kern TS, Dubyak GR, Subauste CS (2017) CD40 in retinal Muller cells induces P2X7-dependent cytokine expression in macrophages/microglia in diabetic mice and development of early experimental diabetic retinopathy. Diabates 66:483–493CrossRefGoogle Scholar
  31. Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrell MI, Friedlander M (2006) Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest 116:3266–3276CrossRefPubMedPubMedCentralGoogle Scholar
  32. Santisteban MM, Ahmari N, Carvajal JM, Zingler MB, Qi Y, Kim S, Joseph J, Garcia-Pereira F, Johnson RD, Shenoy V, Raizada MK, Zubcevic J (2015) Involvement of bone marrow cells and neuroinflammation in hypertension. Circ Res 117:178–191CrossRefPubMedPubMedCentralGoogle Scholar
  33. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D'Amato R, Sullivan R, D'Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111PubMedGoogle Scholar
  34. Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Lofqvist C, Hellstrom A, Smith LEH (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51:2813–2826CrossRefPubMedPubMedCentralGoogle Scholar
  35. Stone J, Itin A, Alon T, Pe'Er J, Gnessin H, Chan-Ling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 15:4738–4747CrossRefGoogle Scholar
  36. Vanhaesebrouck S, Daniels H, Moons L, Vanhole C, Carmeliet P, De Zegher F (2009) Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration. Pediatr Res 65:307–310CrossRefPubMedGoogle Scholar
  37. Wang H, Smith GW, Yang Z, Jiang Y, McCloskey M, Greenberg K, Geisen P, Culp WD, Flannery J, Kafri T, Hammond S, Hartnett ME (2013) Short hairpin RNA-mediated knockdown of VEGFA in Muller cells reduces intravitreal neovascularization in a rat model of retinopathy of prematurity. Am J Pathol 183:964–974CrossRefPubMedPubMedCentralGoogle Scholar
  38. Xu W, Yin J, Sun L, Hu Z, Dou G, Zhang Z, Wang H, Guo C, Wang Y (2017) Impact of minocycline on vascularization and visual function in an immature mouse model of ischemic retinopathy. Sci Rep 7:7535CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yin J, Xu WQ, Ye MX, Zhang Y, Wang HY, Zhang J, Li Y, Wang YS (2017) Up-regulated basigin-2 in microglia induced by hypoxia promotes retinal angiogenesis. J Cell Mol Med 21(12):3467–3480CrossRefPubMedPubMedCentralGoogle Scholar
  40. Zhang SX, Ma JH, Bhatta M, Fliesler SJ, Wang JJ (2015) The unfolded protein response in retinal vascular diseases: implications and therapeutic potential beyond protein folding. Prog Retin Eye Res 45:111–131CrossRefPubMedGoogle Scholar
  41. Zhou Y, Yoshida S, Nakao S, Yoshimura T, Kobayashi Y, Nakama T, Kubo Y, Miyawaki K, Yamaguchi M, Ishikawa K, Oshima Y, Akashi K, Ishibashi T (2015) M2 macrophages enhance pathological neovascularization in the mouse model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 56:4767–4777CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Wenqin Xu
    • 1
  • Zhicha Hu
    • 1
  • Yang Lv
    • 1
  • Guorui Dou
    • 1
  • Zifeng Zhang
    • 1
  • Haiyan Wang
    • 1
  • Yusheng Wang
    • 1
  1. 1.Department of Ophthalmology, Xijing Hospital, Eye Institute of Chinese PLAFourth Military Medical UniversityXi’anPeople’s Republic of China

Personalised recommendations