PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models.

Héloïse Lebas, Sylvaine Guérit, Audrey Picot, Anne Cécile Boulay, Antoine Fournier, Denis Vivien, Martine Cohen Salmon, Fabian Docagne, Isabelle Bardou

Cellular and molecular life sciences : CMLS 2022 May 28

filter terms:

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. 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. 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. 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. © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Citation

Héloïse Lebas, Sylvaine Guérit, Audrey Picot, Anne Cécile Boulay, Antoine Fournier, Denis Vivien, Martine Cohen Salmon, Fabian Docagne, Isabelle Bardou. PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models. Cellular and molecular life sciences : CMLS. 2022 May 28;79(6):323