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Jacqueline Reinhard, Julia Woestmann, Susanne Wiemann, Stephanie C Joachim, Andreas Faissner; Extracellular matrix remodeling and immune activation in glaucomatous PTP-Meg2 deficient mice. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
The molecular mechanisms of glaucomatous RGC degeneration are not fully understood. Previous studies indicate that RGC degeneration is accompanied by extracellular matrix (ECM) remodeling and activation of immune components. Heterozygous (HET) protein tyrosine phosphatase Meg2 (PTP-Meg2) mice exhibit progressive IOP elevation and RGC loss. Here, we evaluate remodeling of the ECM glycoprotein Tenascin-C (TNC), microglia (MG) reactivity and complement activation in PTP-Meg2 HET mice.
TNC immunoreactivity as well as numbers of Iba1+/NOS2+ reactive microglia (MG) and MAC+ cells were assessed by immunohistochemistry in retina and optic nerve (n=3-5/group) of PTP-Meg2 HET and wildtype (WT) littermates at 6, 10 and 28 weeks. Using qRT-PCR analyses, mRNA expression levels of MG and complement factors were quantified in HET and WT retinas at 10 and 28 weeks (n=3-4/group).
TNC immunoreactivity was significantly increased in the retina (p=0.0003) and optic nerve (p=0.03) of glaucomatous PTP-Meg2 HET animals in comparison to WT mice at 28 weeks. In addition, PTP-Meg2 HET mice showed a significantly elevated number of Iba1+/NOS2+ MG in the optic nerve at 28 weeks (p=0.04). In contrast, comparable numbers of Iba1+/NOS2+ MG were observed in the optic nerve of HET and WT mice at 6 (p=0.8) and 10 weeks (p=0.84). NOS2 mRNA expression levels were significantly upregulated in the HET retina at 28 weeks (p=0.04), whereas no expression changes were observed at 10 weeks (p=0.2). MAC+ cells were significantly increased in HET retinas at 28 weeks (p=0.005). No change in the number of MAC+ retinal cells was observed in HET and WT mice at 6 and 10 weeks (p=0.2). An increased number of MAC immunoreactive cells was found in the HET optic nerves at 28 weeks (p=0.008). At 6 and 10 weeks, the number of MAC+ cells was comparable in the WT and HET optic nerve (p=0.5, p=0.2). Expression of the complement components C2, C4 and C5 was significantly upregulated in HET retinas at 28 weeks (p=0.03, p=0.04 and p≤0.001).
The present study showed that RGC degeneration in glaucomatous PTP-Meg2 HET mice leads to an upregulation of the ECM glycoprotein TNC and additionally an increase in microglial reactivity and complement activation. PTP-Meg2 deficient mice may serve as a useful animal model to further analyze the molecular mechanisms of glaucomatous neurodegeneration.
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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