Morbillivirus infection of the mouse central nervous system induces region-specific upregulation of MMPs and TIMPs correlated to inflammatory cytokine expression

Viral infection of the central nervous system (CNS) can result in perturbat ion of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases ( TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological di sorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canin e distemper virus (CDV) was used to study the effect of CNS infection on th e MMP/TIMP balance and cytokine expression. CDV replicates almost exclusive ly in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that alt hough several mouse brain structures were infected, they exhibited a differ ential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampu s, which occurred mainly in neurons and was associated with in situ gelatin olytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, su ggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant regio n-specific large increase in expression of Th1-like cytokines, such as gamm a interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contra sting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures , which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS inte grity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.