Interferon-γ blocks signalling through PDGFRβ in human brain pericytes.

Deidre Jansson,Justin Rustenhoven,Natacha Coppieters,Richard L M Faull,Emma L Scotter,E Scott Graham,Robyn L Oldfield,Leon C D Smyth,Edward W Mee,Mike Dragunow,Peter S Bergin

doi:10.1186/s12974-016-0722-4

Deidre Jansson, Justin Rustenhoven + Show 9 more

Open Access

https://doi.org/10.1186/s12974-016-0722-4

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Abstract

BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are common features of many brain disorders, including Alzheimer’s disease, epilepsy, and motor neuron disease. Inflammation is thought to be a driver of BBB breakdown, but the underlying mechanisms for this are unclear. Brain pericytes are critical cells for maintaining the BBB and are immunologically active. We sought to test the hypothesis that inflammation regulates the BBB by altering pericyte biology.MethodsWe exposed primary adult human brain pericytes to chronic interferon-gamma (IFNγ) for 4 days and measured associated functional aspects of pericyte biology. Specifically, we examined the influence of inflammation on platelet-derived growth factor receptor-beta (PDGFRβ) expression and signalling, as well as pericyte proliferation and migration by qRT-PCR, immunocytochemistry, flow cytometry, and western blotting.ResultsChronic IFNγ treatment had marked effects on pericyte biology most notably through the PDGFRβ, by enhancing agonist (PDGF-BB)-induced receptor phosphorylation, internalization, and subsequent degradation. Functionally, chronic IFNγ prevented PDGF-BB-mediated pericyte proliferation and migration.ConclusionsBecause PDGFRβ is critical for pericyte function and its removal leads to BBB leakage, our results pinpoint a mechanism linking chronic brain inflammation to BBB dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0722-4) contains supplementary material, which is available to authorized users.

Highlights

Neuroinflammation and blood-brain barrier (BBB) disruption are common features of many brain disorders, including Alzheimer’s disease, epilepsy, and motor neuron disease
Consistent with previous reports of tumour necrosis factor alpha (TNFα) and interleukin-1beta (IL-1β) treatment in pericytes, both Plateletderived growth factor receptor-beta (PDGFRβ) and Alpha smooth muscle actin (αSMA) protein expression were reduced after chronic treatment of either cytokine [51] (Additional file 1: Figure S1)
PDGFRβ is critical for pericyte function but is reduced in brain disorders that exhibit BBB and blood-spinal cord barrier (BSCB) damage

Summary

Introduction

Neuroinflammation and blood-brain barrier (BBB) disruption are common features of many brain disorders, including Alzheimer’s disease, epilepsy, and motor neuron disease. Inflammation and disruption of the blood-brain barrier (BBB) are present in virtually all neurodegenerative diseases, as well as epilepsy, stroke, and traumatic brain injury [1,2,3,4]. Inflammation in models of AD, multiple sclerosis (MS), and stroke can induce BBB damage and exacerbate and even precede neuropathology [12,13,14]. In the case of amyotrophic lateral sclerosis, several studies have shown that blood-spinal cord barrier (BSCB) dysfunction precedes motor neuron damage, and both the BBB and BSCB have been posed as a potential therapeutic target for early treatment [15, 16]. Reparation of the BSCB in a model of motor neuron disease slows disease progression [17]

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