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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Endothelial α6β4 integrin protects during experimental autoimmune encephalomyelitis-induced neuroinflammation by maintaining vascular integrity and tight junction protein expression

Authors: Jennifer V. Welser, Sebok K. Halder, Ravi Kant, Amin Boroujerdi, Richard Milner

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Extracellular matrix (ECM) proteins play critical functions regulating vascular formation and function. Laminin is a major component of the vascular basal lamina, and transgenic mice deficient in astrocyte or pericyte laminin show defective blood-brain barrier (BBB) integrity, indicating an important instructive role for laminin in cerebral blood vessels. As previous work shows that in the normal brain, vascular expression of the laminin receptor α6β4 integrin is predominantly restricted to arterioles, but induced on all vessels during neuroinflammation, it is important to define the role of this integrin in the maintenance of BBB integrity.

Methods

α6β4 integrin expression was analyzed using dual immunofluorescence (dual-IF) of brain sections taken from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To investigate the role of endothelial α6β4 integrin, transgenic mice lacking β4 integrin in endothelial cells (β4-EC-KO) and wild-type (WT) littermates were subject to EAE, and clinical score and various neuropathological parameters were examined by immunofluorescence. In addition, β4 integrin null brain endothelial cells (BECs) were examined in culture for expression of tight junction proteins using immunocytochemistry and flow cytometry.

Results

Cerebrovascular expression of β4 integrin was markedly upregulated during EAE progression, such that by the acute stage of EAE (day 21), the vast majority of blood vessels expressed β4 integrin. In the EAE model, while the β4-EC-KO mice showed the same time of disease onset as the WT littermates, they developed significantly worse clinical disease over time, resulting in increased clinical score at the peak of disease and maintained elevated thereafter. Consistent with this, the β4-EC-KO mice showed enhanced levels of leukocyte infiltration and BBB breakdown and also displayed increased loss of the endothelial tight junction proteins claudin-5 and ZO-1. Under pro-inflammatory conditions, primary cultures of β4KO BECs also showed increased loss of claudin-5 and ZO-1 expression.

Conclusions

Taken together, our data suggest that α6β4 integrin upregulation is an inducible protective mechanism that stabilizes the BBB during neuroinflammatory conditions.
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Metadata
Title
Endothelial α6β4 integrin protects during experimental autoimmune encephalomyelitis-induced neuroinflammation by maintaining vascular integrity and tight junction protein expression
Authors
Jennifer V. Welser
Sebok K. Halder
Ravi Kant
Amin Boroujerdi
Richard Milner
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0987-2

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