DAMPs drive Fibroinflammatory Changes in the glaucomatous ONH

Purpose: The optic nerve head (ONH) is well known to be the initial site of glaucomatous damage. However, the molecular mechanisms initiating this pathology are not fully understood. To further understand the initiating factors in glaucomatous damage we utilized a novel mouse model of glaucoma, B6.EDA+/+ mice, that constitutively express FN containing the EDA domain (FN+EDA). FN+EDA is a known damage associated molecular pattern (DAMP) that activates toll-like receptor 4 (TLR4) and elicits a fibro-inflammatory response. Results: B6.EDA+/+ mice exhibit significantly higher IOP, loss of RGCs, thinning of the RNFL, and progressive levels of ON damage at 12 months and 22 months of age compared to C57BL/6J controls. Protein expression of DAMPs FN+EDA and biglycan were significantly increased in B6.EDA+/+ mice compared to C57BL/6J controls. GSEA analysis identified significantly up- and down-regulated gene groupings at both 12 months and 22 months of age, and IHC staining demonstrated significant increases of IFNα, IFNβ, and pSTAT1 expression in B6.EDA+/+ mice compared to C57BL/6J controls. Conclusions: Our study characterizes glaucomatous changes to the retina, ON, and ONH over the course of two years and identifies novel molecular pathways associated with these pathophysiological changes. These data indicate time specific DAMP production and immune system signaling in a novel mouse model of glaucoma.