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B. J. Raisler, L. Xu, R. King; Bead Array Cytokine Profiling in Oxygen Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5050.
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© ARVO (1962-2015); The Authors (2016-present)
Recent evidence has suggested that macrophages function both in the establishment and regression of neovascular vessels in the oxygen induced retinopathy (OIR) model. Specifically, MCP-1 -/- mice deficient in macrophage signalling have a prolonged response to the OIR model with delayed onset and regression of neovascular vessels (Davies and Powers, ARVO 2005). Further studies demonstrated that macrophages were indeed co-localized with neovascular tufts during both the establishment and regression phase of the OIR model (Davies et al, Mol. Vis 2006). Using a multi-cytokine bead array, we investigate the signaling pattern in the eyes of wild-type, MCP-1 -/- and CCR2 -/- macrophage signaling deficient mice.
Neonatal mice (wild-type, MCP-1 -/-, and CCR2 -/-) were housed in 75% oxygen from postnatal day 7 through day 12 as described in the widely used mouse OIR model. At time points immediately preceeding and following the return to room air, animals were killed and ocular tissue was rapidly isolated. The posterior segment of the eye was dissected and the choroid/RPE separated from the neural retina. RPE/Choroid and neural retina tissues were collected at the following time points: postnatal day 11, 12, 13, 15, 18, 21, 24, 26, 28, and 35 (n=3 for each time point). Each sample was analyzed by BioRad bead array for the following 17 cytokines: IL-1 alpha, IL-4, IL-6, IL-10, IL-12 (p70), GM-CSF, IFN-gamma, MCP-1, MIP-1 alpha, MIP-1 beta, TNF-alpha, IL-18, bFGF, M-CSF, MIP-2, PDGF-BB, and VEGF.
Mice deficient in macrophage signaling have an altered cytokine profile from their wild-type counterparts. In addition to the anticipated changes in direct macrophage signaling pathways via measured MCP-1, MIP-1 alpha and beta, other cytokines were impacted including IL-1 alpha, IL-6, TNF-alpha, IL-18, and VEGF. Levels of cytokines measured in macrophage signaling deficient mice were delayed by a period of 3-7 days from their wild-type counterparts.
Global cytokine profiling over the period of neovascular establishment and regression can provide key guidance in understanding the regulation of pathological angiogenesis in the eye. Complex interactions of the inflammatory processes contribute to the establishment of neovascular pathology. Later in the model, macrophage function appears to be important to regression of vessels, perhaps via apoptotis. The differential temporal expression of the panel of cytokines depicts a pattern reflective of the delayed onset and regression of macrophage deficient mice. These data represent the first broad look at global cytokine activity for the time frame of the OIR model.
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