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Alice Claudia Wyse Jackson, Sarah Louise Roche, Thomas G Cotter; The role of microglia-photoreceptor crosstalk in retinal cell protection. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1192.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies have highlighted the involvement of microglia and inflammation to the progression of retinal diseases. Norgestrel, a synthetic progesterone, has been reported to have novel anti-apoptotic properties in mouse models of retinitis pigmentosa. This study aimed to elucidate the role of microglia and inflammation in the neuroprotection offered by Norgestrel. We show that Norgestrel administration reduces inflammation in rd10 mice. This correlated with reduced microglial number and activation, as well as increased photoreceptor cell survival through inhibition of multiple cell-death pathways.
Nursing rd10 mothers were put on a Norgestrel supplemented diet (80mg/kg) when pups were aged P10. Mice were sacrificed from P15-P40 and harvested for analysis by rt-qPCR, western blotting, immunofluorescence and retinal explanting (n=3). Rd10 retinas were also harvested for primary microglial cell cultures and 661W photoreceptor cells were utilised for in vitro studies (n=4). Two-tailed Student’s t-test was used for statistical analysis.
Norgestrel-treated rd10 mice showed a significant delay in disease progression up to P40 (p<0.005). Norgestrel significantly decreased chemokine (MCP1, MCP3, MIP1α, MIP1β, p<0.001) release in rd10 mice, compared to control. Activated microglia were found in the outer nuclear layer (ONL) of P20 control mice, whereas microglial number and activation were decreased in the ONL of Norgestrel-treated mice. Dampened microglial activity correlated with decreased cytokine production (TNFα, Il-1β, p<0.001). Prevention of microglial infiltration to the ONL is hypothesised to prevent photoreceptor degeneration through initiation of various cell death pathways, for Norgestrel treated mice showed decreased caspase-3 and PARP cleavage, photoreceptor lysosomal formation and calpain activation. Interestingly, Norgestrel showed no capacity to work on the Fracktalkine-CX3CR1 photoreceptor-microglial pathway, which has been implicated in potentiating disease progression.
Norgestrel is emerging as a promising therapy for the treatment of degenerative retinal diseases. Promoting cell survival, we report here for the first time, its ability to prevent microglial infiltration in to the ONL. Norgestrel's inability to work on the Fracktalkine-CX3CR1 pathway however may lead to eventual cell loss, and thus highlights the potential for a combination treatment.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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