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Kyle Marra, Salome Murinello, Felicitas Bucher, Edith Aguilar, Martin Friedlander; Characterization of the neuroinflammatory response in the oxygen-induced retinopathy model of ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3462.
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The oxygen-induced retinopathy (OIR) model of ischemic retinopathy has been used to test the anti-angiogenic potential of various compounds, including VEGF antagonists. While neuroinflammation has been implicated in the pathophysiology of human ischemic retinopathies such as proliferative diabetic retinopathy, it has not been systematically studied. This study aimed to characterize cytokine and immune cell activation in the OIR model.
OIR was induced in C57BL/6J mice via hyperbaric oxygen exposure from p7-p12. Tissues were collected at p12, p14, p17 and p21. Infiltration of immune cells (monocytes, neutrophils, T cells, and B cells) and activation of microglia were investigated by flow cytometry. qPCR analysis was performed to investigate expression levels of several cytokines known to be involved in modulating immune responses. The role of particular cytokines was investigated by injection of recombinant protein or neutralizing antibodies at p12 with immunohistochemical quantification of neovascularization (NV) at p17.
During the neovascular phase from p12 to p14, there was no infiltration of immune cells, microglia did not express any activation markers investigated, and LTA, CCL17, CCL3, CCL4, and CXCL10 mRNA levels were up-regulated. During the vascular repair phase from p17 to p21, infiltration of macrophages and neutrophils was observed and mRNA levels of CCL11, CCL2 and IL-6 were up-regulated. Consistently, when we injected neutralizing antibodies for LTA and CCL17, NV was delayed. When we injected recombinant CCL2 and CCL11, we saw reduced NV.
Our study demonstrates a role of previously unexplored inflammatory proteins in ischemic retinopathy. Surprisingly, we saw that microglia activation and myeloid cell recruitment did not occur during the neovascular phase (p12-p14) in the OIR model, which coincided with qPCR findings of elevated immunosuppressive cytokines at p12 and p14. In addition, we found that microglia activation and myeloid cell recruitment began during the repair phase (p17-p21), coinciding with the upregulation of pro-inflammatory cytokines. These trends suggest that certain inflammatory proteins in the OIR model may be promoting tissue repair rather than pathology, a result that highlights the need to further investigate immunologic targets for treating ocular disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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