Hyaloid Vasculature as a Major Source of STAT3+ (Signal Transducer and Activator of Transcription 3) Myeloid Cells for Pathogenic Retinal Neovascularization in Oxygen-Induced Retinopathy

Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):e367-e379. doi: 10.1161/ATVBAHA.120.314567. Epub 2020 Oct 29.

Abstract

Objective: Myeloid cells are critically involved in inflammation-induced angiogenesis, although their pathogenic role in the ischemic retina remains controversial. We hypothesize that myeloid cells contribute to pathogenic neovascularization in retinopathy of prematurity through STAT3 (signal transducer and activator of transcription 3) activation. Approach and Results: Using the mouse model of oxygen-induced retinopathy, we show that myeloid cells (CD45+IsolectinB4 [IB4]+) and particularly M2-type macrophages (CD45+ Arg1+), comprise a major source of STAT3 activation (pSTAT3) in the immature ischemic retina. Most of the pSTAT3-expressing myeloid cells concentrated at the hyaloid vasculature and their numbers were strongly correlated with the severity of pathogenic neovascular tuft formation. Pharmacological inhibition of STAT3 reduced the load of IB4+ cells in the hyaloid vasculature and significantly reduced the formation of pathogenic neovascular tufts during oxygen-induced retinopathy, leading to improved long-term visual outcomes (ie, increased retinal thickness and scotopic b-wave electroretinogram responses). Genetic deletion of SOCS3 (suppressor of cytokine signaling 3), an endogenous inhibitor of STAT3, in myeloid cells, enhanced pathological and physiological neovascularization in oxygen-induced retinopathy, indicating that myeloid-STAT3 signaling is crucial for retinal angiogenesis.

Conclusions: Circulating myeloid cells may migrate to the immature ischemic retina through the hyaloid vasculature and contribute to retinal neovascularization via activation of STAT3. Understanding how STAT3 modulates myeloid cells for vascular repair/pathology may provide novel therapeutic options in pathogenic angiogenesis.

Keywords: cytokines; inflammation; macrophages; myeloid cells; retina.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anthraquinones / pharmacology
  • Disease Models, Animal
  • Female
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxygen*
  • Phosphorylation
  • Retinal Neovascularization / etiology
  • Retinal Neovascularization / metabolism*
  • Retinal Neovascularization / pathology
  • Retinal Neovascularization / prevention & control
  • Retinal Vessels / drug effects
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology
  • Retinopathy of Prematurity / etiology
  • Retinopathy of Prematurity / metabolism*
  • Retinopathy of Prematurity / pathology
  • Retinopathy of Prematurity / prevention & control
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism

Substances

  • Anthraquinones
  • LLL12 compound
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Sulfonamides
  • Suppressor of Cytokine Signaling 3 Protein
  • Oxygen