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S. S. Atherton, Y. Liu, M. Zheng, M. A. Fields, H. M. Cathcart; TNF Expressing HSV-1 Recombinant Promotes Apoptosis in Inflammatory and Retinal Parenchymal Cells During Acute Retinal Necrosis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4286.
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To study the role of TNF in HSV-1 induced acute retinal necrosis (ARN).
BALB/c mice were injected with 2.5 × 104 pfu of a TNF-expressing recombinant of HSV-1 (KOSTNF) or with an equivalent amount of parental HSV-1 (KOS6β) via anterior chamber (AC) inoculation. At different times post inoculation (p.i.), mice were sacrificed and the contralateral eyes were enucleated and immunohistochemistry was performed to determine the extent of virus infection, apoptosis, and inflammatory cell infiltrate.
At day 6 p.i., infection was not observed in the retina of the contralateral eyes in either the KOSTNF injected group or the KOS6β injected group. Three of 5 mice and 5 of 5 mice in the KOSTNF group were infected compared with 1 of 5 and 2 of 5 mice in the KOS6β group on day 8 p.i. and day 10 p.i., respectively. ARN in the uninoculated eye occurred earlier and was more severe in the KOSTNF group compared with the KOS6β group. TUNEL assay revealed more apoptotic cells in the contralateral retina of KOSTNF infected mice than in the KOS6β infected mice; in the former, the majority of the apoptotic cells were virus infected. Triple staining for TUNEL, HSV-1 and TNF revealed more TNF in the virus infected areas of the retina in KOSTNF infected mice compared with KOS6β infected mice. In KOSTNF infected mice, 10%-20% of the TUNEL+ cells were also positive for TNF and HSV-1, and if not colocalized with TUNEL+ cells, TNF+ cells were frequently located in proximity to the TUNEL+ cells. The F4/80, CD45 and Mac-1 staining suggested that some of the TUNEL+ cells could be infiltrating macrophages and other inflammatory cells as well as retinal parenchyma cells such as microglia and neurons.
Although TNF may exert protective effects in the CNS during HSV-1 infection, in the retina, overexpression of this proinflammatory cytokine increases the speed and extent of retinal damage by induction of apoptosis in infiltrating inflammatory cells as well as in cells of the retinal parenchyma through autocrine and/or paracrine effects.
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