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). Lumican-null mice are somewhat protected in an LPS-sepsis challenge, but develop exacerbated disease when challenged with bacterial infections of the cornea and lungs. Our work in progress has identified regulations of other TLRs by lumican and other SLRPs, such as biglycan and decorin. We are using mice with targeted deletions of lumican, biglycan or and decorin to understand how their deficiencies affect development and functions of neutrophils, macrophages, dendritic cells, B and T cells under homeostatic conditions and inflammation. We are collaborating with our colleagues in NYU Microbiology and Pathology and the NYU Vaccine Center to understand the SLRP-immune cell interactions at a molecular level and their relevance to vaccine response, bacterial and viral infections and autoimmunity in humans.