Abstract
BackgroundPlasminogen activation is a ubiquitous source of fibrinolytic and proteolytic activity. Besides its role in prevention of thrombosis, plasminogen is involved in inflammatory reactions in the central nervous system. Plasminogen has been detected in the cerebrospinal fluid (CSF) of patients with inflammatory diseases; however, its origin remains controversial, as the blood–CSF barrier may restrict its diffusion from blood.MethodsWe investigated the origin of plasminogen in CSF using Alexa Fluor 488–labelled rat plasminogen injected into rats with systemic inflammation and blood–CSF barrier dysfunction provoked by lipopolysaccharide (LPS). Near-infrared fluorescence imaging and immunohistochemistry fluorescence microscopy were used to identify plasminogen in brain structures, its concentration and functionality were determined by Western blotting and a chromogenic substrate assay, respectively. In parallel, plasminogen was investigated in CSF from patients with Guillain-Barré syndrome (n = 15), multiple sclerosis (n = 19) and noninflammatory neurological diseases (n = 8).ResultsEndogenous rat plasminogen was detected in higher amounts in the CSF and urine of LPS-treated animals as compared to controls. In LPS-primed rats, circulating Alexa Fluor 488–labelled rat plasminogen was abundantly localized in the choroid plexus, CSF and urine. Plasminogen in human CSF was higher in Guillain-Barré syndrome (median = 1.28 ng/μl (interquartile range (IQR) = 0.66 to 1.59)) as compared to multiple sclerosis (median = 0.3 ng/μl (IQR = 0.16 to 0.61)) and to noninflammatory neurological diseases (median = 0.27 ng/μl (IQR = 0.18 to 0.35)).ConclusionsOur findings demonstrate that plasminogen is transported from circulating blood into the CSF of rats via the choroid plexus during inflammation. Our data suggest that a similar mechanism may explain the high CSF concentrations of plasminogen detected in patients with inflammation-derived CSF barrier impairment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0154-y) contains supplementary material, which is available to authorized users.
Highlights
Vessel wall fibrinolytic activity and pericellular proteolysis in tissues requires plasminogen binding and transformation into plasmin at the surface of fibrin, cells or the extracellular matrix by either the tissue-type plasminogen activator or the urokinase-type plasminogen activator [1]
Our results show that circulating plasminogen enters the cerebrospinal fluid (CSF) space during blood–CSF barrier dysfunction induced by systemic inflammation, suggesting that plasminogen found in the CSF of patients with inflammatory neurological disorders originates from circulating blood
Rat CSF plasminogen was efficiently transformed into plasmin; its active concentration appeared to be directly related to the amount of plasminogen detected in CSF samples by Western immunoblotting (P = 0.0045, Mann–Whitney U test) (Figure 2C)
Summary
Vessel wall fibrinolytic activity and pericellular proteolysis in tissues requires plasminogen binding and transformation into plasmin at the surface of fibrin, cells or the extracellular matrix by either the tissue-type plasminogen activator (tPA) or the urokinase-type plasminogen activator (uPA) [1]. Pericellular proteolysis in the central nervous system (CNS) is involved in development, regeneration of nervous tissues, neuronal and synaptic plasticity and the inflammatory response [6,7,8,9]. Trace amounts of plasminogen have been reported in normal human cerebrospinal fluid (CSF), whereas raised concentrations have been detected in patients with meningitis [11], subarachnoid haemorrhage [12] and multiple sclerosis [13]. The question has not been settled as to whether plasminogen in CSF originates from circulating blood or is expressed in the CNS, as suggested by the presence of mRNA in mouse brain [14,15] or by its synthesis by rat microglial cells in culture [16]. Plasminogen has been detected in the cerebrospinal fluid (CSF) of patients with inflammatory diseases; its origin remains controversial, as the blood–CSF barrier may restrict its diffusion from blood
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