Selective inhibition of matrix metalloproteinase-9 in CD4+ T-cells reduces clinical severity in a murine model of Multiple Sclerosis.

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 leukocyte trafficking, 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 studies, we demonstrate that the MMP-9 is important for homeostatic maintenance as well as a robust antigenic stimulation. Upon activation, CD4+ T-cells treated with an MMP-9 inhibitor demonstrate a reduced ability to enter cell cycle, proliferate, and produce cytokines. In addition, RNA-seq analysis highlight key proteins associated with the T-cell receptor signaling pathway that are impacted. Furthermore, treatment of EAE mice resulted in reduced clinical severity. This reduction is associated with a treatment regimen that starts on Day 7 as opposed to Day 0, suggesting that CD4+ T cells are more sensitive to the impact of MMP-9 inhibition compared to other immune cells. These results emphasize the importance of MMP-9 as a therapeutic target in CD4+ T-cell mediated autoimmune diseases.