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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2021

Open Access 01-12-2021 | Tissue Plasminogen Activator | Research

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

Authors: Pauline Hélie, Celia Camacho-Toledano, Léonie Lesec, Célia Seillier, Antonio J. Miralles, Maria Cristina Ortega, Sylvaine Guérit, Héloïse Lebas, Isabelle Bardou, Virginia Vila-del Sol, Denis Vivien, Brigitte Le Mauff, Diego Clemente, Fabian Docagne, Olivier Toutirais

Published in: Journal of Neuroinflammation | Issue 1/2021

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Abstract

Background

Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis. It is released by endothelial cells, but also expressed by neurons and glial cells in the central nervous system (CNS). Interestingly, this enzyme also contributes to pathological processes in the CNS such as neuroinflammation by activating microglia and increasing blood–brain barrier permeability. Nevertheless, its role in the control of adaptive and innate immune response remains poorly understood.

Methods

tPA effects on myeloid and lymphoid cell response were studied in vivo in the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis and in vitro in splenocytes.

Results

tPA-/- animals exhibited less severe experimental autoimmune encephalomyelitis than their wild-type counterparts. This was accompanied by a reduction in both lymphoid and myeloid cell populations in the spinal cord parenchyma. In parallel, tPA increased T cell activation and proliferation, as well as cytokine production by a protease-dependent mechanism and via plasmin generation. In addition, tPA directly raised the expression of MHC-II and the co-stimulatory molecules CD80 and CD86 at the surface of dendritic cells and macrophages by a direct action dependent of the activation of epidermal growth factor receptor.

Conclusions

Our study provides new insights into the mechanisms responsible for the harmful functions of tPA in multiple sclerosis and its animal models: tPA promotes the proliferation and activation of both lymphoid and myeloid populations by distinct, though complementary, mechanisms.
Appendix
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Metadata
Title
Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses
Authors
Pauline Hélie
Celia Camacho-Toledano
Léonie Lesec
Célia Seillier
Antonio J. Miralles
Maria Cristina Ortega
Sylvaine Guérit
Héloïse Lebas
Isabelle Bardou
Virginia Vila-del Sol
Denis Vivien
Brigitte Le Mauff
Diego Clemente
Fabian Docagne
Olivier Toutirais
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2021
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-021-02102-5

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