Selective inhibition of matrix metalloproteinase-9 reduces clinical severity in a murine model of Multiple Sclerosis via a reduced immune response

Abstract

Abstract Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix components. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including Multiple Sclerosis (MS). During MS, CD4+ T-cells activated in the periphery penetrate the blood-brain barrier (BBB), recruit immune cells, initiate destruction of the myelin sheath, and cause axonal loss. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. In EAE, MMP-9 is required for penetration of the BBB and generation of auto-antigens. Recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In our in vitro studies of immune cells we assessed their response to mitogen following treatment with an MMP-9 inhibitor (MMP-9I). We demonstrated that the MMP-9 intracellular activity is important for homeostatic maintenance as well as a robust immune response. Our in vivo studies using MMP9I resulted in reduced disease severity and a reduction in key EAE hallmarks, weight loss and clinical score. Furthermore, proliferation of immune cells in the periphery following disease induction was reduced and the cellular infiltrates across the BBB. These results further emphasize the importance of MMP-9 as a therapeutic target in autoimmune diseases in addition to its well-established extracellular roles. Thus, it presents a two pronged approach to the therapeutic treatment of autoimmunity.