Extracellular matrix interactions with immune cells and regulations of host response to infections and inflammation

infection and inflammationWe study an ECM proteoglycan family called the small leucine repeat-rich proteoglycans (SLRPs). Our studies led to a paradigm shift in understanding the functioning of SLRPs. Initially believed to be only structural proteins, we have demonstrated that SLRPs are also cell signaling proteins of the ECM. Levels of many SLRPs, including a specific SLRP called lumican, increase in infections and inflammation of the cornea, lungs, skin and the gut in humans. As structural proteins SLRPs interact with collagen fibrils and regulate collagen assembly and connective structure. However, newly synthesized SLRPs, or those released from a remodeling ECM during infections and inflammation, can interact with cell surface receptors to regulate immune cell functions. Our studies have shown that mice systemically lacking lumican, when challenged with bacterial infections of the cornea {Shao, 2013 #8619} or the lungs{Shao, 2012 #12143}, are unable to clear the infection, and display more severe disease symptoms. We discovered that lumican released by activated fibroblasts, binds to the surface of neutrophils. These interactions at the cell surface promote neutrophil migration {Lee, 2009 #1890}, and aid toll-like receptor 4 on macrophages {Wu, 2007 #9918} and dendritic cells to respond to bacterial LPS. We are also investigating the role of SLRPs in the regulation of other TLRs. Using gene-targeted mice deficient in lumican, biglycan or decorin, we are investigating their role in bacterial and viral infections and autoimmunity.