Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

Abstract

Viral infection of the central nervous system (CNS) can result in perturbation 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 disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested 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 region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting 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 integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…In several infection models, the infiltration of activated T-lymphocytes into the brain is a wellcharacterized parameter linked to the development of encephalitis and neurodegeneration (Irani and Griffin, 1991;Khuth et al, 2001;Marten et al, 2003). A priming process initiated by a low number of infiltrating encephalitogenic T-lymphocytes could set the stage for a second greater wave of invading effector cells, as observed in multiple sclerosis patients and associated animal models (Engelhardt and Ransohoff, 2005;Norman and Hickey, 2005).…”

“…Such a cytoskeletal reconfiguration requires a complex and still not completely defined array of intracellular signaling pathways implicating second messengers, several kinases and Rho family small GTPases (del Pozo et al, 1999; 5 reaction with the infiltration of T lymphocytes, the expression of the cytokines TNF, IL6, IFN and IL-4 associated with the disruption of the tissue inhibitor of the metalloprotease TIMP/ metalloprotease MMP balance (Benscsik et al, 1996;Khuth et al, 2001) capable of modifying vascular permeability.…”

Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain

“…In the cortex expression of TIMP-2, mRNA is observed predominantly in neurons [23,25]. Notably, TIMP-2 expression appears to be neither upregulated by neuronal depolarization nor by pathological conditions that activate TIMP-1 [23,31,32]. TIMP-3 is expressed at the lowest level in the adult rat brain [21], although its mRNA has been found in the cortex [33], cerebellum [17], thalamus, olfactory bulb [22], and brain stem [18].…”

“…It is thus interesting that MMP-2 is expressed at a much higher level during postnatal cortical development than in the adult neocortex (Dzwonek et al, unpublished). Inducible expression of MMP-2 in glia has also been noted following brain ischemia [20,42], kainate (KA) treatment as well as traumatic and viral brain injury [32,37,40,[47][48][49]. Interestingly, Asahi et al [50] showed that MMP-2 gene knockout in mice has no effect on brain injury after permanent and transient focal ischemia.…”

“…This notion appears surprising in the context of the previously described data implicating MMP-9 in neuronal plasticity. However, although under the variety of neurodegenerative conditions (ischemia, brain trauma, viral infections, amyotrophic lateral sclerosis, ALS, Parkinson's disease, PD, Alzheimer's disease, AD) MMP-9 still remains mainly neuronal in origin, it is not clear whether it is expressed by the neurons prone to death and/or those attempting to recover from the damage [12,20,31,32,43,[57][58][59]. As it has recently been pointed out that both possibilities should be equally considered [60].…”