S100A8 and A9 proteins regulate expression of key genes for inflammation and wound healing.

Abstract

Pterygium is a common ocular surface disease characterized by centripetal invasion of the conjunctival epithelium onto the cornea. The disease has a wing-shaped phenotype accompanied by inflammatory infiltrate and accumulation of proteases and extracellular matrix components. S100A proteins are involved in activating the immune system, and previous studies have implicated S100A8/A9 in many ocular surface diseases such as meibomian gland dysfunction, dry eye, preservative induced epitheliopathy and chemical injury. Since a variety of matrix and inflammatory proteins are dysregulated in pterygium, in this thesis, I attempt to determine if S100A protein is a master regulator that triggers these changes by adding S100A8, A9 and heterocomplex S100A8/A9 to cultured conjunctival fibroblasts. A variety of transcript changes were examined. Inflammatory chemokine (Chemokine (C-X-C motif) ligand 1), matrix proteins (Vimentin, Biglycan, and Gelsolin), Annexin-A2, Thymosin beta-4 and Ras-related protein Rab 10 molecules known to be upregulated in pterygium, were found to be induced by S100A8, A9 and A8/A9.These genes are therefore possible downstream of S100A8/A9 in diseases. Chymase-1 and Serpin peptidase inhibitor, clade A member 1 (SERPINA1) are known to be downregulated in pterygium but are upregulated by S100A9 protein, suggesting presence of other disease pathways. Intervention in S100A proteins may be impactful on a wide variety of ocular surface diseases by reducing disease mediators.