PROJECT SUMMARY Multiple sclerosis (MS) is a significant neurological disease affecting millions of people in the US. This disease is believed to be driven by autoimmune activities against the myelin sheath in the central nervous system. MS is modeled by the experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of MS. Interleukin-1 (IL-1) signaling has been shown to be essential for the pathogenesis of EAE, but which cell-type specific IL-1 receptor mediated processes are required for EAE are unclear. In addition, matrix metalloproteinase 9 (MMP-9) is known to play an important role in mediating the breakdown of the blood brain barrier during EAE. Our preliminary results show endothelial IL-1 receptor type 1 (eIL-1R1) and T cell IL-1 receptor type 1 (TcIL-1R1) may both be required to mediate different aspects of the EAE pathogenesis, and IL-1R1 and MMP-9 may amplify each other’s function during EAE. This application is designed to: 1) Demonstrate eIL-1R1 and TcIL-1R1 combine to mediate EAE induction; 2) Identify the roles of MMP-9 in eIL-1R1 and TcIL-1R1 mediated autoimmune processes; and 3) Determine whether IL-1R1 and MMP-9 specific inhibitors synergistically block EAE induction and progression.