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Susanne Wiemann, Jacqueline Reinhard, Sabrina Reinehr, Stephanie C Joachim, Andreas Faissner; Loss of the extracellular matrix protein Tenascin-C in an autoimmune glaucoma mouse model causes a diminished microglial response. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3727.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is characterized by death of retinal ganglion cells (RGCs) and optic nerve degeneration. Recent studies indicate that extracellular matrix (ECM) remodeling is involved in glaucomatous neurodegeneration, although the functional relevance is not understood yet. In this study, we used the intraocular pressure (IOP)-independent experimental autoimmune glaucoma (EAG) mouse model to investigate the role of the ECM protein Tenascin-C (TNC), an important modulator of the immune response. We analyzed RGC loss and microglia response in the EAG model in wild type (WT) and TNC knockout (KO) mice.
WT (WT ONA) and KO (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate, Freund`s adjuvant and pertussis toxin. Control groups (CO) received sodium chloride (WT CO; KO CO). Booster injections with half of the original dose were given after 4 and 8 weeks. IOP was measured regularly in all groups (n=8/group). The number of Brn3a+ RGCs and Iba1+ microglia was immunohistochemically analyzed on retinal flat-mounts 10 weeks after immunization (n=6/group). Moreover, glial mRNA expression of Iba1 and Nos2 was investigated via quantitative real-time PCR (n=5/group). Groups were compared using one-way ANOVA followed by Tukey`s post hoc test or the pairwise fixed reallocation and randomization test.
All groups showed a physiological IOP. WT ONA (p=0.0003) and KO ONA mice (p=0.01) exhibited a significant loss of RGCs compared to the CO groups. A significantly enhanced number of Iba1+ microglia was found in WT ONA retinae compared to WT CO (p=0.03). In contrast, analysis of microglia in KO ONA retinae revealed a significantly decreased number compared to the KO CO group (p=0.01). Additionally, Iba1 (p=0.04) and Nos2 (p=0.03) mRNA expression was significantly increased in WT ONA compared to WT CO retinae, while a comparable mRNA level was observed in KO ONA in comparison to KO CO retinae (p>0.05).
In this study, we found a significant RGC loss in WT ONA and KO ONA mice. WT ONA animals showed a significantly increased microglia infiltration and glial marker expression, indicating an increased microglial response. Most interestingly, a significantly reduced microglial response was observed in KO ONA retinae, suggesting that TNC signaling is an important modulator of microglia in glaucomatous neurodegeneration.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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