The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention

Abstract

BackgroundExtracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA−/−), or the urokinase PA receptor (uPAR−/−). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1).ResultsEAE was aggravated in uPA−/− and uPAR−/− mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation.ConclusionsCumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. Furthermore, the successful amelioration of EAE by PAI-1 treatment suggests that the PA system can be considered a potential site for therapeutic intervention in the treatment of neuroimmune diseases.

Urokinase receptor and tissue plasminogen activator as immediate‐early genes in pentylenetetrazole‐induced seizures in the mouse brain

“…Functionally, post‐seizure uPA expression is supposed to be neuroprotective (Cho et al., ; Gur‐Wahnon et al., ; Lahtinen et al., ). The pivotal role of uPA system in brain recovery was also shown for ischemic injury (Diaz, Merino, Manrique, Cheng, & Yepes, ; Diaz et al., ; Merino, Diaz, Manrique, Cheng, & Yepes, ).…”

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

“…30,31 Plasmin was also found to play a deleterious role in neuro-inflammation and injury to the blood brain barrier and brain parenchyma in vivo . 4,32,34 Therefore, in the present study, we investigated the potential relationship between plasmin and the PDGF-BB/PDGFR-β system. First, the plasmin inhibitor, EACA, was co-injected with autologous arterial blood into the right basal ganglia of mice.…”

White matter pathways as both a target and mediator of health behaviors

“…This is important since it provides hope for recovery if improvements in health reduce the levels of circulating inflammatory cytokines. For example, at the cellular level, plasminogen activator inhibitors have successfully stopped the progression of demyelination in rodent models of MS. 143 Therefore, any interventions that can result in the reduction of plasminogen activator signaling could potentially attenuate any progressive effects on white matter tissue. While it is not clear yet whether targeting plasminogen activator through nonpharmaceutical interventions can effectively reduce the levels of plasminogen in the brain, studies have effectively targeted and manipulated nitric oxide levels through behavioral interventions.…”