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Increased expression of M-CSF and IL-13 in vitreous of patients with proliferative diabetic retinopathy: implications for M2 macrophage-involving fibrovascular membrane formation
  1. Shigeo Yoshida1,
  2. Yoshiyuki Kobayashi1,
  3. Takahito Nakama1,
  4. Yedi Zhou1,
  5. Keijiro Ishikawa1,
  6. Ryoichi Arita1,
  7. Shintaro Nakao1,
  8. Masanori Miyazaki1,
  9. Yukio Sassa1,
  10. Yuji Oshima1,
  11. Kenji Izuhara2,
  12. Toshihiro Kono3,
  13. Tatsuro Ishibashi1
  1. 1Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
  2. 2Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan
  3. 3Department of Ophthalmology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
  1. Correspondence to Dr Shigeo Yoshida, Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; yosida{at}


Purpose We recently demonstrated that M2 macrophages were involved in the development of fibrovascular membranes (FVM) associated with proliferative diabetic retinopathy (PDR) possibly through the induction of periostin. The purpose of this study was to determine whether macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-13, inducers of the M2 polarisation of macrophages from monocytes, are elevated in the vitreous of patients with PDR, and whether M2-polarised macrophages induce periostin production.

Methods We measured the levels of M-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, IL-13, soluble (s)CD163, periostin and vascular endothelial growth factor by sandwich ELISA in vitreous samples collected from 61 eyes of 47 patients with PDR, and 39 eyes of 36 patients with non-diabetic ocular diseases (control group). Human monocytes were polarised in vitro with GM-CSF, interferon-γ, and lipopolysaccharide for M1 macrophages, and M-CSF, IL-4, and IL-13 for M2 macrophages. Quantitative real-time PCR was used to determine the mRNA level of periostin.

Results The concentrations of M-CSF and IL-13 in the vitreous were significantly higher in patients with PDR than in non-diabetic controls (p<0.0001). There was a strong positive correlation between the vitreous concentrations of M-CSF and sCD163 and periostin. The mean vitreous level of IL-13 was significantly higher in eyes with FVMs than in those without FVMs (epicentre only). In vitro studies showed that M2-polarlised macrophages significantly increased the expression of the mRNA of periostin.

Conclusions These findings indicate that the M2 polarisation of macrophages is induced by M-CSF and IL-13 in diabetic retinas. The presence of M-CSF and IL-13 would then promote FVM formation by periostin production.

  • Retina
  • Vitreous

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