Persistent Inflammation Subverts Thrombospondin-1–Induced Regulation of Retinal Angiogenesis and Is Driven by CCR2 Ligation

Mei Chen, David A. Copland, Jiawu Zhao, Jian Liu, John V. Forrester, Andrew D. Dick, Heping Xu

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Neovascular retinal disease is a leading cause of blindness orchestrated by inflammatory responses. Although noninfectious uveoretinitis is mediated by CD4(+) T cells, in the persistent phase of disease, angiogenic responses are observed, along with degeneration of the retina. Full clinical manifestation relies on myeloid-derived cells, which are phenotypically distinct from, but potentially sharing common effector responses to age-related macular degeneration. To interrogate inflammation-mediated angiogenesis, we investigated experimental autoimmune uveoretinitis, an animal model for human uveitis. After the initial acute phase of severe inflammation, the retina sustains a persistent low-grade inflammation with tissue-infiltrating leukocytes for over 4 months. During this persistent phase, angiogenesis is observed as retinal neovascular membranes that arise from inflamed venules and postcapillary venules, increase in size as the disease progresses, and are associated with infiltrating arginase-1(+) macrophages. In the absence of thrombospondin-1, retinal neovascular membranes are markedly increased and are associated with arginase-1(-) CD68(+) macrophages, whereas deletion of the chemokine receptor CCR2 resulted in reduced retinal neovascular membranes in association with a predominant neutrophil infiltrate. CCR2 is important for macrophage recruitment to the retina in experimental autoimmune uveoretinitis and promotes chronicity in the form of a persistent angiogenesis response, which in turn is regulated by constitutive expression of angiogenic inhibitors like thrombospondin-1. This model offers a new platform to dissect the molecular and cellular pathology of inflammation-induced ocular angiogenesis.
Original languageEnglish
Pages (from-to)235-245
Number of pages11
JournalAmerican Journal of Pathology
Volume180
Issue number1
Early online date07 Nov 2011
DOIs
Publication statusPublished - Jan 2012

Keywords

  • Animals
  • Cytokines
  • Cytokines: biosynthesis
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CCR2
  • Receptors, CCR2: deficiency
  • Receptors, CCR2: metabolism
  • Receptors, CCR2: physiology
  • Retinal Neovascularization
  • Retinal Neovascularization: etiology
  • Retinal Neovascularization: metabolism
  • Retinal Neovascularization: pathology
  • Retinitis
  • Retinitis: etiology
  • Retinitis: metabolism
  • Retinitis: pathology
  • Thrombospondin 1
  • Thrombospondin 1: deficiency
  • Thrombospondin 1: physiology
  • Uveitis
  • Uveitis: etiology
  • Uveitis: metabolism
  • Uveitis: pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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