Inflammation Research

, Volume 68, Issue 12, pp 1071–1079 | Cite as

Upregulated CD200 in pre-retinal proliferative fibrovascular membranes of proliferative diabetic retinopathy patients and its correlation with vascular endothelial growth factor

  • Yaguang Hu
  • Anming Xie
  • Qiaochu ChengEmail author
Original Research Paper


Objective and design

The objective was to determine the expression of CD200 in the pre-retinal proliferative fibrovascular membranes (PFVM) of patients with proliferative diabetic retinopathy (PDR) and to clarify its correlation with vascular endothelial growth factor (VEGF) and corresponding receptors.


PFVM samples were collected by vitrectomy from 14 patients with PDR, and 11 non-diabetic patients who accepted vitrectomy for idiopathic epiretinal membranes removal. The expression of CD200, VEGF,VEGF-R1 and VEGF-R2 was measured via qPCR and immunofluorescent staining.


The mRNA level of CD200 was significantly higher in PDR patients than that in control patients. Meanwhile, CD200 and CD31 were found co-located and statistically associated in PFVM of PDR patients. The mRNA levels of VEGF, VEGF-R1 and VEGF-R2 were also significantly higher in PDR patients. Moreover, statistical association was found between CD200 and VEGF, VEGF-R1 in mRNA levels. But there was no significant correlationship between CD200 and VEGF-R2.


These results suggest a significantly increased expression of CD200 in PFVM of patients with PDR and present a crucial association between CD200 and VEGF-involved pathway. It represents a potential therapy that interfering with CD200 may inhibit the VEFG expression and neovascular formation in PDR patients.


CD200 Proliferative diabetic retinopathy Proliferative fibrovascular membrane Vascular endothelial growth factor 



Shaanxi provincial government provided financial support in the form of the Natural Science Foundation of Shaanxi Province (No. 2019JQ-953).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.


  1. 1.
    Gliem M, Finger RP, Fimmers R, Brinkmann CK, Holz FG. Issa PC Treatment of choroidal neovascularization due to angioid streaks: a comprehensive review. Retina (Phila Pa). 2013;33(7):1300–14.CrossRefGoogle Scholar
  2. 2.
    Loukovaara S, Piippo N, Kinnunen K, Hytti M, Kaarniranta K, Kauppinen A. NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol. 2017; 95:803–8.CrossRefGoogle Scholar
  3. 3.
    Abu El-Asrar AM, Ahmad A, Bittoun E, Siddiquei MM, Mohammad G, Mousa A, et al. Differential expression and localization of human tissue inhibitors of metalloproteinases in proliferative diabetic retinopathy. Acta Ophthalmol. 2017.Google Scholar
  4. 4.
    Ding X, Patel M, Chan CC. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2009;28:1–18.CrossRefGoogle Scholar
  5. 5.
    Karlstetter M, Langmann T. Microglia in the aging retina. Adv Exp Med Biol. 2014;801:207–12.CrossRefGoogle Scholar
  6. 6.
    Dick AD. Doyne lecture 2016: intraocular health and the many faces of inflammation. Eye (Lond). 2017;31:87–96.CrossRefGoogle Scholar
  7. 7.
    Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol Adv Ophthalmol. 2012;124:15–26.CrossRefGoogle Scholar
  8. 8.
    Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol. 1995;113:1538–44.CrossRefGoogle Scholar
  9. 9.
    Kinoshita S, Noda K, Saito W, Kanda A, Ishida S. Vitreous levels of vascular endothelial growth factor-B in proliferative diabetic retinopathy. Acta Ophthalmol. 2016;94:e521–3.CrossRefGoogle Scholar
  10. 10.
    Chen X, Luo S, Liu Y. Coordination skills during vitrectomy in treatment of proliferative diabetic retinopathy. Eye Sci. 2014;29:55–8.PubMedGoogle Scholar
  11. 11.
    Moran EP, Wang ZX, Chen J, Sapieha P, Smith LEH, Ma JX. Neurovascular cross talk in diabetic retinopathy: pathophysiological roles and therapeutic implications. Am J Physiol-Heart C. 2016;311:H738–49.CrossRefGoogle Scholar
  12. 12.
    Capitao M, Soares R. Angiogenesis and inflammation crosstalk in diabetic retinopathy. J Cell Biochem. 2016;117:2443–53.CrossRefGoogle Scholar
  13. 13.
    Weller M, Wiedemann P, Heimann K. Proliferative vitreoretinopathy—is it anything more than wound healing at the wrong place? Int Ophthalmol. 1990;14:105–17.CrossRefGoogle Scholar
  14. 14.
    Campochiaro PA. Pathogenic mechanisms in proliferative vitreoretinopathy. Arch Ophthalmol. 1997;115:237–41.CrossRefGoogle Scholar
  15. 15.
    Tikhonovich MV, Erdiakov AK, Gavrilova SA. Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one. Int Ophthalmol. 2017Google Scholar
  16. 16.
    Hernangomez M, Carrillo-Salinas FJ, Mecha M, Correa F, Mestre L, Loria F, et al. Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. Curr Pharm Des. 2014;20:4707–22.CrossRefGoogle Scholar
  17. 17.
    Horie S, Robbie SJ, Liu J, Wu WK, Ali RR, Bainbridge JW, et al. CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization. Sci Rep. 2013;3:3072.CrossRefGoogle Scholar
  18. 18.
    Taylor S, Calder CJ, Albon J, Erichsen JT, Boulton ME, Morgan JE. Involvement of the CD200 receptor complex in microglia activation in experimental glaucoma. Exp Eye Res. 2011;92:338–43.CrossRefGoogle Scholar
  19. 19.
    Jiang L, Xu F, He W, Chen L, Zhong H, Wu Y, et al. CD200Fc reduces TLR4-mediated inflammatory responses in LPS-induced rat primary microglial cells via inhibition of the NF-kappaB pathway. Inflamm Res. 2016;65:521–32.CrossRefGoogle Scholar
  20. 20.
    Xu Y, Cheng Q, Yang B, Yu S, Xu F, Lu L, et al. Increased sCD200 levels in vitreous of patients with proliferative diabetic retinopathy and its correlation With VEGF and proinflammatory cytokines. Invest Ophthalmol Vis Sci. 2015;56:6565–72.CrossRefGoogle Scholar
  21. 21.
    Subhi Y, Krogh Nielsen M, Molbech CR, Oishi A, Singh A, Nissen MH, et al. CD11b and CD200 on circulating monocytes differentiate two angiographic subtypes of polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2017;58:5242–50.CrossRefGoogle Scholar
  22. 22.
    Liu JQ, Talebian F, Wu L, Liu Z, Li MS, Wu L, et al. A critical role for CD200R signaling in limiting the growth and metastasis of CD200 + Melanoma. J Immunol. 2016;197:1489–97.CrossRefGoogle Scholar
  23. 23.
    Zhao F, Gandorfer A, Haritoglou C, Scheler R, Schaumberger MM, Kampik A, et al. Epiretinal cell proliferation in macular pucker and vitreomacular traction syndrome: analysis of flat-mounted internal limiting membrane specimens. Retina (Phila Pa). 2013;33:77–88.CrossRefGoogle Scholar
  24. 24.
    Smiddy WE, Maguire AM, Green WR, Michels RG, de la Cruz Z, Enger C, et al. Idiopathic epiretinal membranes. Ultrastructural characteristics and clinicopathologic correlation. Ophthalmology. 1989;96:811–20 (Discussion 821).CrossRefGoogle Scholar
  25. 25.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods. 2001;25:402–8.CrossRefGoogle Scholar
  26. 26.
    Zhang XX, He FF, Yan GL, Li HN, Li D, Ma YL, et al. Neuroprotective effect of cerebralcare granule after cerebral ischemia/reperfusion injury. Neural regen Res. 2016;11:623–9.CrossRefGoogle Scholar
  27. 27.
    Gorczynski RM. CD200:CD200R-mediated regulation of immunity. ISRN Immunol. 2012;2012:18.CrossRefGoogle Scholar
  28. 28.
    Wright GJ, Cherwinski H, Foster-Cuevas M, Brooke G, Puklavec MJ, Bigler M, et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol. 2003;171:3034–46.CrossRefGoogle Scholar
  29. 29.
    Rijkers ES, de Ruiter T, Baridi A, Veninga H, Hoek RM, Meyaard L. The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Mol Immunol. 2008;45:1126–35.CrossRefGoogle Scholar
  30. 30.
    Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290:1768–71.CrossRefGoogle Scholar
  31. 31.
    Jenmalm MC, Cherwinski H, Bowman EP, Phillips JH, Sedgwick JD. Regulation of myeloid cell function through the CD200 receptor. J Immunol. 2006;176:191–9.CrossRefGoogle Scholar
  32. 32.
    Holmannova D, Kolackova M, Kondelkova K, Kunes P, Krejsek J, Andrys C. CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function. Acta Med (Hradec Kralove). 2012;55:12–7.CrossRefGoogle Scholar
  33. 33.
    Koning N, Bo L, Hoek RM, Huitinga I. Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol. 2007;62:504–14.CrossRefGoogle Scholar
  34. 34.
    Walker DG, Dalsing-Hernandez JE, Campbell NA, Lue LF. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp Neurol. 2009;215:5–19.CrossRefGoogle Scholar
  35. 35.
    Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging. 2006;27:717–22.CrossRefGoogle Scholar
  36. 36.
    Dick AD, Carter D, Robertson M, Broderick C, Hughes E, Forrester JV, et al. Control of myeloid activity during retinal inflammation. J Leukoc Biol. 2003;74:161–6.CrossRefGoogle Scholar
  37. 37.
    Taylor N, McConachie K, Calder C, Dawson R, Dick A, Sedgwick JD, et al. Enhanced tolerance to autoimmune uveitis in CD200-deficient mice correlates with a pronounced Th2 switch in response to antigen challenge. J Immunol. 2005;174:143–54.CrossRefGoogle Scholar
  38. 38.
    Barclay AN, Wright GJ, Brooke G, Brown MH. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 2002;23:285–90.CrossRefGoogle Scholar
  39. 39.
    Belkin DA, Mitsui H, Wang CQ, Gonzalez J, Zhang S, Shah KR, et al. CD200 upregulation in vascular endothelium surrounding cutaneous squamous cell carcinoma. JAMA Dermatol. 2013;149:178–86.CrossRefGoogle Scholar
  40. 40.
    Hamuro J, Toda M, Asada K, Hiraga A, Schlotzer-Schrehardt U, Montoya M, et al. Cell homogeneity indispensable for regenerative medicine by cultured human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2016;57:4749–61.CrossRefGoogle Scholar
  41. 41.
    Cai J, Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond). 2002;16:242–60.CrossRefGoogle Scholar
  42. 42.
    Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006;39:469–78.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of OphthalmologyThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina

Personalised recommendations