Tissue-type plasminogen activator (tPA) is one of the principal activators of fibrinolysis in mammalian systems; however, we have shown that tPA also regulates cell physiology by binding to cell-surface receptors, such as the N-methyl-D-aspartate receptor (NMDA-R) and LDL Receptor-related Protein-1 (LRP1). This result is important because tPA is an FDA-approved drug and the effects of tPA on cell physiology do not require tPA enzymatic activity. In macrophages, tPA suppresses inflammatory responses initiated by Toll-like Receptors (TLRs). Thus, tPA may represent an important regulator of innate immunity. We have a number of important goals. First, we seek to understand the effects of tPA on macrophage cell-signaling. Next, we seek to understand the activity of tPA in common diseases in which chronic inflammation may play an important role, including chronic neuropathic pain, inflammatory bowel disease, and Alzheimer’s Disease.