Regulation of matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) genes during JHMV infection of the central nervous system.

Abstract

The central nervous system (CNS) is refractive to many aspects of the immune system primarily due to its limited ability to repair damage induced by the cytopathic mechanisms deployed by most immune cells. A primary obstacle to CNS inflammation is the blood-brain-barrier (BBB), which limits entry of immune cells into the CNS. To pass the BBB, inflammatory cells release matrix metalloproteinases (MMPs); a growing family of proteases with overlapping substrate specificities for components of the extracellular matrix (reveiwed by Kieseier et al. 1999). MMPs break down the extracellular matrix surrounding the endothelial layer of BBB thereby permitting peripheral immune cells to traverse the BBB and migrate through the parenchyma of the CNS in response to inflammatory signals. To limit potential damage resulting from infiltration of inflammatory cells, MMP activity is tightly regulated at both the level of gene expression and proenzyme activation as well as by expression of a second gene family, the tissue inhibitors of MMPs (TIMPs). TIMPs act as competitive inhibitors for the active sites of MMPs and thus limit inflammatory infiltrates.