Keratoconus is a degenerative thinning of the ECM of the cornea. The cornea is a specialized ECM-rich protective barrier tissue of the eye made up of collagens, glycoproteins, and proteoglycans, like lumican, keratocan, biglycan and decorin. In keratoconus the corneal ECM deteriorates, becomes thin and protrudes. Patients suffer from high astigmatism, scarring and progressive loss of vision. Keratoconus is managed by contact lens use and UV cross-linking of collagens (CXL) to temporarily strengthen the ECM connective tissue at the early stages. In advanced stages cornea-transplants are required, making keratoconus a leading cause for cornea-transplants worldwide. Although influenced by multiple environmental stressors, keratoconus has a strong genetic basis where multiple genetic variants individually or in combination are hypothesized to be causal.
Pioneering work in our laboratory has identified and characterized a group of small leucine-rich repeat proteoglycans (SLRP) of the ECM. Proteoglycans are glycoproteins post-translationally modified with glycosaminoglycan side chains. We focused on a prototype SLRP, lumican. It is a keratan sulfate proteoglycan in the cornea where it regulates collagen fibril structure and corneal transparency. The glycoprotein form of lumican is widely present in many tissues where it has other immunoregulatory functions. Our prior work on inflammatory bowel disease, corneal and lung infections show that lumican is induced under inflammatory conditions, and that it interacts with β2 integrin to promote neutrophil and macrophage chemotaxis. Recently, we found that lumican interacts with CD14 on the surface of macrophages to regulate toll-like receptor (TLR) 4 response to bacterial lipopolysaccharides (LPS).