A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis

Abstract

Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA ؊/؊ ) and urokinase plasminogen activator receptor (uPAR ؊/؊ ), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. tPA ؊/؊ mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. In contrast, uPAR ؊/؊ mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis. Serine protease activity in multiple sclerosis (MS) is considered to play a major role in the disturbance of the blood-brain barrier and subsequent leukocyte entry leading to inflammation as well as causing myelin breakdown.1,2 Significant up-regulation of urokinase-type plasminogen activator (uPA) receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) are among the earliest detectable signs of inflammatory demyelination.

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

“…A delay in neuroinflammation accompanied by a higher capacity for fibrinolysis resulted in a milder disease in PAI-1 -/-mice with no clinical relapses or recurrent neuropathology. In contrast, immunocytochemistry of representative spinal cord samples from WTs had a similar disease pattern to mice of the pure ABH strain [13] with marked inflammation, impairment of fibrinolysis, focal demyelination and axonal degeneration, confirming results in our recent report [1].…”

“…In control WT and PAI-1 -/-mice, myelin staining was dense and complete in the white matter of the spinal cord (not shown, as per our prior report [1]). There were no differences in MBP staining between the genotypes at any stage of CREAE, except at 40 dpi, where PAI-1 -/-mice were still in disease remission and had normal appearing myelin staining while WTs were relapsing and had some evidence of demyelination in the spinal cord, specifically in areas of perivascular inflammation with macrophage infiltration (Figure 2G,H).…”

“…The total number of perivascular cuffs was determined in a spinal cord longitudinal section area of 4 cm 2 as described previously [1]. The average cuff count was taken from a total of three slides from three different mice per time point.…”

“…Fibrin is deposited on axons in MS and in chronic experimental allergic encephalomyelitis (EAE) [1,2], and up-regulation of components of the plasminogen activator (fibrinolytic) system correlates with onset of inflammation and migration of leucocytes into the brain parenchyma [3,4]. Influx of fibrin(ogen) is associated with up-regulated activity of tissue plasminogen activator (tPA), the key fibrinolytic enzyme.…”

Central nervous system inflammatory demyelinating diseases with stroke-like onset and their responses to thrombolysis

“…Using mice deficient in tissuetype plasminogen activator (tPA-/-), East et al investigated the involvement of the PA system on the clinical and pathological features of EAE. They found that tPA-/-mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls [6]. A better understanding of the mechanism of inhibition of coagulation-fibrinolysis system facilitate disease pathogenesis may present a new strategy for pharmacological intervention in inflammatory demyelinating diseases.…”