Dysregulation of Blood-Brain Barrier and Exacerbated Inflammatory Response in Cx47-Deficient Mice after Induction of EAE.

Filippos Stavropoulos,Irene Sargiannidou,Elena Georgiou,Kleopas A Kleopa

doi:10.3390/ph14070621

Abstract

Induction of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), in connexin 32 (Cx32) or Cx47 knockout (KO) mice with deficiency in oligodendrocyte gap junctions (GJs) results in a more severe disease course. In particular, Cx47 KO EAE mice experience an earlier EAE onset and more pronounced disease severity, accompanied by dysregulated pro-inflammatory responses preceding the disease manifestations. In this study, analysis of relevant pro-inflammatory cytokines in wild type EAE, Cx32 KO EAE, and Cx47 KO EAE mice revealed altered expression of Vcam-1 preceding EAE [7 days post injection (dpi)], of Ccl2 at the onset of EAE (12 dpi), and of Gm-csf at the peak of EAE (24 dpi) in Cx47 KO EAE mice. Moreover, Cx47 KO EAE mice exhibited more severe blood-spinal cord barrier (BSCB) disruption, enhanced astrogliosis with defects in tight junction formation at the glia limitans, and increased T-cell infiltration prior to disease onset. Thus, Cx47 deficiency appears to cause dysregulation of the inflammatory profile and BSCB integrity, promoting early astrocyte responses in Cx47 KO EAE mice that lead to a more severe EAE outcome. Further investigation into the role of oligodendrocytic Cx47 in EAE and multiple sclerosis pathology is warranted.

Highlights

Multiple sclerosis (MS) is an acquired, autoimmune, and demyelinating disease of the central nervous system (CNS) with a reported prevalence of more than 2.2 million individuals worldwide from 1990 to 2016 [1]
Even though the cause of the disease has not yet been fully elucidated, increased permeability of the blood–brain barrier (BBB) and peripheral immune cell infiltration into the CNS are the earliest aberrations observed in brains of MS patients, and are the early events implicated in EAE development [7,8]
Crosstalk between astrocytes and oligodendrocytes is achieved via gap junctions (GJs), which are specialized membrane structures whose building blocks are connexins (Cxs)

Summary

Introduction

Multiple sclerosis (MS) is an acquired, autoimmune, and demyelinating disease of the central nervous system (CNS) with a reported prevalence of more than 2.2 million individuals worldwide from 1990 to 2016 [1]. EAE recapitulates the main aspects of MS, including inflammation, activation of astrocytes and microglia, demyelination, and axonal loss [4,5,6]. Even though the cause of the disease has not yet been fully elucidated, increased permeability of the blood–brain barrier (BBB) and peripheral immune cell infiltration into the CNS are the earliest aberrations observed in brains of MS patients, and are the early events implicated in EAE development [7,8]. CNS glia cells, including oligodendrocytes, astrocytes, and microglia, are important for maintaining homeostasis and are directly involved in the pathogenesis of MS. Crosstalk between astrocytes and oligodendrocytes is achieved via gap junctions (GJs), which are specialized membrane structures whose building blocks are connexins (Cxs).

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