Abstract
PurposeTo determine the involvement of sympathetic activity in choroidal neovascularization (CNV) using laser-induced CNV in a mouse model.MethodsWe investigated changes in the proportions of intraocular lymphocytes, granulocytes, and three macrophage subtypes (Ly6Chi, Ly6Cint, and Ly6Clo) after laser injury in mice using flow cytometry, and evaluated CNV lesion size in mice lacking inflammatory cells. Further, we evaluated the lesion size in mice administered the β3 receptor antagonist, splenic-denervated and splenectomized mice. We also assessed changes in the proportions of intraocular macrophages and peripheral blood monocytes in splenic-denervated and splenectomized mice. Lastly, lesion size was compared between splenic-denervated mice with or without adoptive transfer of macrophages following laser injury. After Ly5.1 mice spleen-derived Ly6Chi cells were transferred into Ly5.2 mice, the proportions of intraocular Ly5.1+Ly6Chi cells were compared.ResultsIn WT mice, the proportion of CD4+ T cells recruited into the eye increased progressively from day 3 to day 7 after laser injury, whereas, intraocular CD8+ T cells did not change significantly. Proportions of B220+ cells, granulocytes, and two subtypes of intraocular macrophages (Ly6Chi and Ly6Clo) peaked at day 3 following laser injury. In contrast, Ly6Cint/loCD64+ subtype showed a significantly higher percentage at day 7 after laser injury. There were no differences in lesion size between CD4–/–or Rag2–/–mice and controls, whereas lesion size was significantly reduced in CCR2−/− mice and clodronate liposome-treated mice. CNV lesion area was significantly reduced in mice with β3 blocker treatment, splenic-denervated and splenectomized mice compared with controls. Intraocular Ly6Chi macrophages were also reduced by splenic denervation or splenectomy. Adoptive transfer of spleen-derived Ly6Chi cells increased the lesion size in splenic-denervated mice. Compared with controls, intraocular donor-derived Ly6Chi cells recruited into the eye were reduced in splenic-denervated and splenectomized mice.ConclusionsAlthough lymphocytes had little effect on CNV formation, Ly6Chi macrophages/monocytes exacerbated CNV in mice. Sympathetic activity might contribute to CNV via the recruitment of macrophages to the eye.
Highlights
In recent studies, inflammation has been found to play an important role in the development of choroidal neovascularization (CNV) [1] in both experimental and clinical settings
There were no differences in lesion size between CD4–/–or Rag2 deficient (Rag2–/–)mice and controls, whereas lesion size was significantly reduced in chemokine receptor type 2 (CCR2)−/− mice and clodronate liposometreated mice
Sympathetic activity might contribute to CNV via the recruitment of macrophages to the eye
Summary
Inflammation has been found to play an important role in the development of choroidal neovascularization (CNV) [1] in both experimental and clinical settings. In experimental models, granulocyte infiltration was found to promote laser-induced CNV [2]. There are reports that intraocular injection of macrophages reduces CNV size [6]. These findings suggest that the role of macrophages in CNV is critical and complex and may depend on the age of experimental animals and the age and subtypes of macrophages. A few studies have suggested that T cells contribute to CNV formation. Tsutsumi-Miyahara et al found that T cells had little effect on CNV formation in a laser-induced model [8]. The precise contributions of specific lymphocyte subtypes to the regulation of angiogenesis in the eye remain unclear
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