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

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Abstract

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.

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Availability of data and materials

The datasets of the current study are available from the corresponding author on reasonable request.

Abbreviations

BBB:

Blood brain barrier

CNS:

Central nervous system

CTCF:

Corrected total cell fluorescence

EAE:

Experimental autoimmune encephalomyelitis

KO:

Knockout

MS:

Multiple sclerosis

NSP:

Neuroserpin

PAI-1:

Type-1 plasminogen activator inhibitor

PAS:

Plasminogen activation system

PLG:

Plasminogen

PN-1:

Protease nexin 1

TAFI:

Thrombin-activatable fibrinolysis inhibitor

tPA:

Tissue-type plasminogen

WT:

Wild type

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Acknowledgements

This project was supported by grants from the French Ministry of Higher Education, the INSERM (French National Institute for Health and Medical Research), the regional Council of Normandy, the ARSEP foundation and the FRM (Fondation pour la recherche médicale). We thank Dr Paul Declerck for the gift of PAI-1 blocking antibody.

Funding

This project was supported by grants from the French Ministry of Higher Education, the INSERM (French National Institute for Health and Medical Research), the regional Council of Normandy, the ARSEP foundation and the FRM (Fondation pour la recherche médicale).

Author information

Author notes

  1. Fabian Docagne

    Present address: Département de l’information scientifique et de la communication (DISC), INSERM, 75654, Paris cedex 13, France

  2. Fabian Docagne and Isabelle Bardou have equal contribution.

Authors and Affiliations

  1. Normandie 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

    Héloïse Lebas, Sylvaine Guérit, Audrey Picot, Antoine Fournier, Denis Vivien, Fabian Docagne & Isabelle Bardou

  2. Collège de France, Center for Interdisciplinary Research in Biology (CIRB)/Centre National de la Recherche Scientifique CNRS, Unité Mixte de Recherche 7241/Institut National de la Santé et de la Recherche Médicale INSERM, U1050/75231, Paris CEDEX 05, France

    Anne Cécile Boulay & Martine Cohen Salmon

  3. Department of Clinical Research, Caen University Hospital, CHU Caen, Caen, France

    Denis Vivien

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Contributions

HL designed the experiments, performed in vitro and in vivo studies, analyzed data, and participated in manuscript preparation. SG analyzed data and participated in manuscript preparation. AP performed reactive astrogliosis and axonal damage experiments and analyzed data. AF generated P-sel+ and P-sel− tissues. A-CB set up and performed FISH study. DV drafted the manuscript. MC-S gave expertise in the design of FISH study and drafted the article. FD designed the study and wrote the article. IB designed the study, analyzed data and wrote the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Isabelle Bardou.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

Animal experiments were performed in accordance with French ethical laws (Decree 87/848) and European guidelines (Directive 2010/63/UE) for the care and use of laboratory animals. Experiments were undertaken in the housing and laboratories (approval #F14118001) and have been approved by the ethics committee no. 52 on animal experiments (CENOMEXA) and by the French Ministry of Research under the project license number #10799. All experiments were performed following the ARRIVE guidelines (www.nc3rs.org.uk), including randomization of treatment as well as analysis blind to the treatment.

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Supplementary Information

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18_2022_4340_MOESM1_ESM.pdf

Supplementary file1 Additional file 1: Figure S1. PAS gene expression in forebrain, cerebellum and spinal cord during the course of MOG-induced EAE. Gene expression of a-c tPA, d-f NSP, g-i PN-1, j TAFI, k, l PAI-1 and m-o PLG in a, d, g, j, m the spinal cord, b, e, h, k, n the cerebellum and c, f, i, l, o the forebrain of mice during the course of MOG-induced EAE. RT-qPCR results expressed as mean ± SEM, n=5 per condition. Kruskal-Wallis test followed by FDR post-hoc test: * and § indicate significant difference (p < 0.05) compared to Sham and Pre-On respectively, Δ indicates other significant differences (p < 0.05) between specific stages. tPA: tissue-type plasminogen activator; NSP: Neuroserpin; PN-1: protease nexin-1; PLG: Plasminogen; TAFI: thrombin-activatable fibrinolysis inhibitor; PAI-1: type-1 plasminogen activator inhibitor. Pre-On: pre-onset; On: onset; Su: surge; Ch: chronic as depicted in Fig. 1a. (PDF 235 KB)

18_2022_4340_MOESM2_ESM.pdf

Supplementary file2 Additional file 2: Figure S2.PAS gene expression in forebrain, cerebellum and spinal cord during the course of PLP-induced EAE. Gene expression of a-c tPA, d-f NSP, g-i PN-1, j TAFI, k, l PAI-1 and m, n PLG in a, d, g, j, m the spinal cord, b, e, h, k, n the cerebellum and c, f, i, l the forebrain of mice during the course of PLP-induced EAE. RT-qPCR results expressed as mean ± SEM, n=5 per condition. Kruskal-Wallis test followed by FDR post-hoc test: *, §, #, † indicate significant difference (p < 0.05) compared to Sham, Pre-On, Rem and Rel respectively, Δ indicates other significant differences (p < 0.05) between specific stages. tPA: tissue-type plasminogen activator; NSP: Neuroserpin; PN-1: protease nexin-1; PLG: Plasminogen; TAFI: thrombin-activatable fibrinolysis inhibitor; PAI-1: type-1 plasminogen activator inhibitor. Pre-On: pre-onset; On: onset; Sc1/2/3/4/2R: score 1/2/3/4/2 remitting; Rem: remission; Rel: relapse as depicted in Fig. 1d. (PDF 295 KB)

18_2022_4340_MOESM3_ESM.pdf

Supplementary file3 Additional file 3: Figure S3: PAI-1 immunostaining quantification in white matter spinal cord sections during the course of MOG-induced EAE model. a Representative PAI-1 immunostaining (red) in cervical, high thoracic, low thoracic and lumbar sections of spinal cord from Sham and MOG-induced EAE mice for each stage of the disease (DAPI: blue). b Quantification of PAI-1 immunostaining coverage in cervical, high thoracic, low thoracic and lumbar sections of spinal cord from Sham and MOG-induced EAE mice. Histograms show mean ± SEM, n=3 per condition. Kruskal-Wallis test followed by FDR post-hoc test: * indicates significant difference (p < 0.05) compared to Sham, Δ indicates other significant differences (p < 0.05) between specific stages. Sc1/2/3/4: score 1/2/3/4. Scale bars: 50µm. (PDF 496 KB)

18_2022_4340_MOESM4_ESM.pdf

Supplementary file4 Additional file 4: Figure S4: PAI-1 immunostaining quantification in white matter spinal cord sections during the course of PLP-induced EAE model. a Representative PAI-1 immunostaining (red) in cervical, high thoracic, low thoracic and lumbar sections of spinal cord from Sham and PLP-induced EAE mice for each stage of the disease (DAPI: blue). b PAI-1 immunostaining coverage in cervical, high thoracic, low thoracic and lumbar sections of spinal cord from Sham and PLP-induced EAE mice. Histograms show mean ± SEM, n=3 per condition. Kruskal-Wallis test followed by FDR post-hoc test: *, §, #, † indicate significant difference (p < 0.05) compared to Sham, Pre-on, Rem and Rel respectively, Δ indicates other significant differences (p < 0.05) between specific stages. Sc1/2/3/4/2R: score1/2/3/4/2 remitting; Rem: remission; Rel: relapse. Scale bars: 50µm. (PDF 672 KB)

18_2022_4340_MOESM5_ESM.pdf

Supplementary file5 Additional file 5: Figure S5: SMI32 immunostaining quantification in white matter spinal cord sections during the course of EAE models. a Representative SMI-32 immunostaining (red) in cervical spinal cord from PAI-1 WT and PAI-1 KO mice at onset (14 dpi), peak (18 dpi) and late stages (45 dpi) during MOG-induced EAE (DAPI: blue). b Corresponding quantifications of axonal damage in cervical spinal cord from PAI-1 WT and PAI-1 KO mice. c Representative SMI32 immunostaining (red) in spinal cord from control and anti-PAI-1 antibody-treated mice at acute (16 dpi), remission (28 dpi) and late stages (45 dpi) during PLP-induced EAE (DAPI: blue). d Corresponding quantifications of axonal damage in spinal cord from control and anti-PAI-1 antibody-treated mice. Histograms show mean ± SEM, n=3 per condition. Mann-Whitney U test; *p < 0.05. Scale bars: 40µm. (PDF 543 KB)

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Lebas, H., Guérit, S., Picot, A. et al. PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models. Cell. Mol. Life Sci. 79, 323 (2022). https://doi.org/10.1007/s00018-022-04340-z

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