DAMPs Drive Fibroinflammatory Changes in the Glaucomatous ONH.

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• The optic nerve head (ONH) is the primary site of glaucomatous damage, but initiating molecular mechanisms remain unclear.
• Fibronectin containing the extra domain A (FN+EDA) is a damage-associated molecular pattern (DAMP) that triggers fibro-inflammatory responses via Toll-like receptor 4.

Purpose of the Study:

• To investigate the role of FN+EDA in initiating glaucomatous damage using a novel mouse model (B6.EDA+/+).
• To characterize the molecular mechanisms and long-term pathophysiological changes in the aging ONH associated with FN+EDA expression.

Main Methods:

• B6.EDA+/+ and C57BL/6J mice were assessed for retinal ganglion cell (RGC) death, retinal nerve fiber layer (RNFL) thickness, and optic nerve (ON) damage at 12 and 22 months.
• Optic nerve head (ONH) tissues were analyzed using laser capture microdissection, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), and immunohistochemical (IHC) staining.

Main Results:

• B6.EDA+/+ mice showed significantly increased intraocular pressure, RGC loss, RNFL thinning, and ON damage compared to controls.
• Elevated protein levels of FN+EDA and biglycan were observed in B6.EDA+/+ mice.
• GSEA revealed significant gene expression changes, and IHC confirmed increased interferon (IFN) and pSTAT1 expression in B6.EDA+/+ mice.

Conclusions:

• This study details 2-year glaucomatous changes in the retina, ON, and ONH, identifying novel molecular pathways.
• The findings highlight the impact of FN+EDA on the aging ONH's fibro-inflammatory response in a new glaucoma mouse model.