Beyond tissue structure, we discovered that collagen-free lumican has a second role in modulating inflammation and immune response (Wu, 2007; Shao2013). Other related members of this proteoglycan family also have dual roles in tissue structure and cell signaling. Lumican interacts with cell surface proteins (integrins, caveolin-1 and CD14) on neutrophils, macrophages, and dendritic cells to promote toll-like receptor (TLR)-4 mediated innate inflammatory signals and defense against bacterial infections. Interestingly, lumican is internalized by immune cells where it regulates vesicular trafficking of receptors and ligands to further control bacterial and viral defense responses (Maiti, 2021). We found that lumican and biglycan, a related chondroitin/dermatan sulfate proteoglycan bind CpG- DNA (TLR9 ligand) and suppress inflammatory signals by controlling when and where within cells TLR9 sees its ligand. This has completely changed our ideas of ECM components from solely regulating the extra cellular niche to one where they modulate plasma membrane properties and intracellular trafficking and immune cell functions. Our ongoing work shows that lumican and biglycan are protective in herpes simplex virus-1 mediated corneal disease. We also discovered that these proteoglycans localize to specific ECM compartments in lymph nodes where they likely regulate antigen presenting cell and immune cell interactions (Maiti, 2025).