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PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models
Héloïse Lebas1, Sylvaine Guérit1, Audrey Picot1
1Normandie Univ, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), 14000, Caen, France.
Background:
In multiple sclerosis (MS), disturbance of the plasminogen activation system (PAS) and blood brain barrier (BBB) disruption are physiopathological processes that might lead to an abnormal fibrin(ogen) extravasation into the parenchyma. Fibrin(ogen) deposits, usually degraded by the PAS, promote an autoimmune response and subsequent demyelination. However, the PAS disruption is not well understood and not fully characterized in this disorder.
Methods:
Here, we characterized the expression of PAS actors during different stages of two mouse models of MS (experimental autoimmune encephalomyelitis-EAE), in the central nervous system (CNS) by quantitative RT-PCR, immunohistofluorescence and fluorescent in situ hybridization (FISH). Thanks to constitutive PAI-1 knockout mice (PAI-1 KO) and an immunotherapy using a blocking PAI-1 antibody, we evaluated the role of PAI-1 in EAE models and its impact on physiopathological processes such as fibrin(ogen) deposits, lymphocyte infiltration and demyelination.
Results:
We report a striking overexpression of PAI-1 in reactive astrocytes during symptomatic phases, in two EAE mouse models of MS. This increase is concomitant with lymphocyte infiltration and fibrin(ogen) deposits in CNS parenchyma. By genetic invalidation of PAI-1 in mice and immunotherapy using a blocking PAI-1 antibody, we demonstrate that abolition of PAI-1 reduces the severity of EAE and occurrence of relapses in two EAE models. These benefits are correlated with a decrease in fibrin(ogen) deposits, infiltration of T4 lymphocytes, reactive astrogliosis, demyelination and axonal damage.
Conclusion:
These results demonstrate that a deleterious overexpression of PAI-1 by reactive astrocytes leads to intra-parenchymal dysfibrinolysis in MS models and anti-PAI-1 strategies could be a new therapeutic perspective for MS.
Insights
Plasminogen activation system (PAS) disruption in multiple sclerosis (MS) involves PAI-1 overexpression by astrocytes, leading to fibrinogen deposits. Inhibiting PAI-1 reduces EAE severity, offering a potential therapeutic strategy for MS.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Pathophysiology of Demyelinating Diseases
Background:
- Multiple sclerosis (MS) involves blood-brain barrier (BBB) disruption and plasminogen activation system (PAS) disturbances.
- Abnormal fibrinogen deposition in the central nervous system (CNS) contributes to MS pathology by promoting autoimmune responses and demyelination.
- The precise role of PAS disruption in MS pathogenesis remains incompletely understood.
Purpose of the Study:
- To characterize the expression of PAS components during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.
- To investigate the role of plasminogen activator inhibitor-1 (PAI-1) in EAE pathogenesis.
- To evaluate the therapeutic potential of targeting PAI-1 in MS.
Main Methods:
- Quantitative RT-PCR, immunohistofluorescence, and FISH were used to analyze PAS gene expression in the CNS of EAE mice.
- PAI-1 knockout (PAI-1 KO) mice and anti-PAI-1 antibody immunotherapy were employed to assess PAI-1's function.
- Assessment of fibrinogen deposition, lymphocyte infiltration, astrogliosis, demyelination, and axonal damage in EAE models.
Main Results:
- PAI-1 was significantly overexpressed in reactive astrocytes during symptomatic EAE, correlating with increased lymphocyte infiltration and fibrinogen deposits.
- Genetic deletion of PAI-1 or PAI-1 blockade via antibody therapy markedly reduced EAE severity and relapse rates.
- Therapeutic benefits were associated with decreased fibrinogen deposition, T4 lymphocyte infiltration, astrogliosis, demyelination, and axonal injury.
Conclusions:
- Overexpression of PAI-1 by reactive astrocytes contributes to intra-parenchymal fibrinogen dysregulation in MS models.
- Targeting PAI-1 with blocking antibodies presents a promising novel therapeutic strategy for multiple sclerosis.
