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Jiangyuan Gao, Sijia Cao, Jing Z. Cui, Eleanor To, Cheryl Y. Gregory-Evans, Kevin Gregory-Evans, Orson L. Moritz, Joanne A. Matsubara; Proinflammatory Events in the P23H-1 Rat Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6455.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this study is to elucidate the role of microglia and inflammatory cytokines in the pigmented Tg(P23H)1Lav (P23H-1) rat model of retinal degeneration.
P23H-1 heterozygous and wild type (WT) Long Evans rats were used in this study. Animals were sacrificed at postnatal day 30, 90, 180 (P30, 90, 180) and eyes were dissected for immunohistochemistry or vitreous sampling. Paraffin embedded tissue sections were probed with antibodies against microglia (OX42), inflammatory cytokines (TNF-α, IL-6) and a pro-apoptotic factor (XAF1). The vitreal levels of selected cytokines were quantified with a Bio-Plex array.
A comparison of the P23H-1 and WT retinas revealed that OX42 immunoreactivity was significantly more robust in P23H-1 at P30 and 90, than at P180. TNF-α, IL-6 and XAF1 immunoreactivity was significantly greater in P23H-1 at all time points. A sub-analysis of the laminar distribution showed that the bulk of the increased immunoreactivity for the cytokines TNF-α and IL-6 as well as the microglial marker, OX42, was present in the GCL and INL. In vitreous samples, the secreted level of MIP-3α, a chemotactic factor, was higher in P23H-1 while IL-7, IFN-γ and MIP-1α levels were surprisingly greater in the WT at P30. A longitudinal analysis of the P23H-1 vitreous samples revealed a steady elevation of TNF-α and a concomitant decline of VEGF and IL-7 from P30 to P180.
Our study demonstrated unique temporal and spatial patterns of microglia, cytokines and apoptosis factors in the pigmented P23H-1 transgenic rat. Intriguingly, it is the inner (GCL, INL) rather than the outer (ONL) retina that exhibited major changes in cytokine expression, suggesting a potential inter-layer regulation loop. In the vitreous microenvironment, overall cytokine secretion is profoundly suppressed in the P23H-1 rat compared to WT. Whether this is due to a general degenerative decline in all retinal layers is hitherto unknown. However, a comparison of the secreted cytokines in the P23H-1 rats’ vitreous from P30 to P180 demonstrated a steady increase in TNF-α and a concomitant decline of VEGF, a putative neuroprotective agent, which may signal a critical imbalance in factors necessary for maintaining retinal homeostasis. The role of inflammatory cytokines in retinal degeneration in the pigmented P23H-1 rat warrants further investigation.
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