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Sha-Mei Liao, Maura Crowley, Steve Louie, Omar Delgado, Natasha Buchanan, Michael Stefanidakis, Bruce Jaffee; HtrA1 regulates the subretinal infiltration of microglia cells in response to bacterial lipopolysaccharides (LPS) and aging in mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3666.
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© ARVO (1962-2015); The Authors (2016-present)
Human genetic studies suggest that HtrA1, a serine protease, may have a role in the pathogenesis of age-related macular degeneration (AMD). Immune-mediated activation of microglia cells might contribute to the pathogenesis of AMD. We examined the effect of HtrA1 on the number of Iba1 positive microglia cells in the subretinal space in response to LPS or in old mice.
LPS (50 ug) was administered intraperitoneally to 7-week-old C57BL/6, HtrA1 KO, or doxycycline-pretreated HtrA1 iTg female mice to induce endotoxin-induced uveitis (EIU). Eyes were collected and dissected at indicated time points. Subretinal microglia cells of RPE/choroid/sclera flat mounts were identified by immuno-staining with fluorescent-labeled Iba1 antibody.
The number of Iba1 positive subretinal microglia cells induced in EIU peaks approximately three days post LPS injection. This induction of subretinal microglia cells by LPS in C57Bl6 HtrA1 wild-type mice was not observed in HtrA1 deficient mice. Conversely, there was about a 30% increase of Iba1 positive microglia cells when the HtrA1 protein was overexpressed in htra1 iTg mice when treated with doxycycline. Since the number of subretinal microglia cells increases with age, the effect of HtrA1 on subretinal microglia cells was examined in aged wild-type and HtrA1 KO mice. The average numbers of subretinal microglia cells in 12- and 19- month old HtrA1 KO mice were 70-80% lower than the values obtained from age-matched, wild-type controls.
The number of subretinal microglia cells induced either by LPS administration or by aging was markedly reduced in the absence of HtrA1 protein. Elevated expression of HtrA1 in the HtrA1 iTg mice resulted in an increase of Iba1positive microglia cells in the subretinal space. These results suggest a positive role of HtrA1 in the regulation of subretinal microglia cells in response to inflammatory signals.
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