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

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

doi:10.1186/s12974-021-02102-5

Abstract

BackgroundTissue 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.MethodstPA 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.ResultstPA-/- 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.ConclusionsOur 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.

Highlights

Tissue plasminogen activator is a serine protease involved in fibrinolysis
Its effects are relevant to the context of Multiple sclerosis (MS): Tissue plasminogen activator (tPA) activity is increased by tenfold in the cerebrospinal fluid (CSF) of MS patients [8], and the protease is found in the perivascular spaces associated to active MS plaques [9]
We have previously shown that tPA, by activating the epidermal growth factor (EGF) receptor (EGFR), has an anti-apoptotic effect over oligodendrocytes [4] and a chemotactic effect on their progenitors that helps remyelination after chemically induced white matter lesions [15]. tPA is able to increase blood–brain barrier (BBB) permeability and helps leukocyte diapedesis [16] by several mechanisms, including the potentiation of endothelial N-methyl-D-aspartate receptors (NMDAR) [17] or tight junction disruption by the modification of occludin phosphorylation [18]

Summary

Introduction

Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis It is released by endothelial cells, and expressed by neurons and glial cells in the central nervous system (CNS). Tissue plasminogen activator (tPA), a serine protease involved in fibrinolysis [2], is mainly produced by endothelial cells of vessels [3], whereas this protease is secreted by several cell types within the CNS such as oligodendrocytes [4], astrocytes [5], or neurons [5, 6]. Pioneer studies reported that tPA activity is increased in EAE [11, 12] and that tPA-deficient mice (tPA-/-) declare EAE later than their wild-type (WT) counterparts, with less severe symptoms in the early phase of the disease, reduced demyelination, axonal damage, microglial activation, and T cell presence in the parenchyma [11]. This indicates that tPA can provide different effects in the EAE course, depending on the phase of the disease and the experimental design

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