Interleukin-1β and interleukin-1 receptor antagonist appear in grey matter additionally to white matter lesions during experimental multiple sclerosis.

Ralf Andreas Linker,Marloes Prins,John G J M Bol,Anne Wierinckx,Rob Binnekade,Fred J H Tilders,Anne-Marie Van Dam,Charlotta Eriksson

doi:10.1371/journal.pone.0083835

Ralf Andreas Linker, Marloes Prins + Show 6 more

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https://doi.org/10.1371/journal.pone.0083835

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Journal: PloS one	Publication Date: Dec 23, 2013
Citations: 33	License type: CC BY 4.0

Affiliation: Amsterdam Neuroscience, Cancer Research Center of Lyon

Abstract

BackgroundMultiple sclerosis (MS) has been mainly attributed to white matter (WM) pathology. However, recent evidence indicated the presence of grey matter (GM) lesions. One of the principal mediators of inflammatory processes is interleukin-1β (IL-1β), which is known to play a role in MS pathogenesis. It is unknown whether IL-1β is solely present in WM or also in GM lesions. Using an experimental MS model, we questioned whether IL-1β and the IL-1 receptor antagonist (IL-1ra) are present in GM in addition to affected WM regions.MethodsThe expression of IL-1β and IL-1ra in chronic-relapsing EAE (cr-EAE) rats was examined using in situ hybridization, immunohistochemistry and real-time PCR. Rats were sacrificed at the peak of the first disease phase, the trough of the remission phase, and at the peak of the relapse. Histopathological characteristics of CNS lesions were studied using immunohistochemistry for PLP, CD68 and CD3 and Oil-Red O histochemistry.ResultsIL-1β and IL-ra expression appears to a similar extent in affected GM and WM regions in the brain and spinal cord of cr-EAE rats, particularly in perivascular and periventricular locations. IL-1β and IL-1ra expression was dedicated to macrophages and/or activated microglial cells, at sites of starting demyelination. The time-dependent expression of IL-1β and IL-1ra revealed that within the spinal cord IL-1β and IL-1ra mRNA remained present throughout the disease, whereas in the brain their expression disappeared during the relapse.ConclusionsThe appearance of IL-1β expressing cells in GM within the CNS during cr-EAE may explain the occurrence of several clinical deficits present in EAE and MS which cannot be attributed solely to the presence of IL-1β in WM. Endogenously produced IL-1ra seems not capable to counteract IL-1β-induced effects. We put forward that IL-1β may behold promise as a target to address GM, in addition to WM, related pathology in MS.

Highlights

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) resulting in a wide range of neurological symptoms including impaired sensory and/or motor function [1]
We studied IL-1b and IL-1 receptor antagonist (IL-1ra) mRNA in the CNS in the early stages of chronic-relapsing EAE (cr-EAE) and related these to some histopathological hallmarks of inflammation in the affected grey and white matter
Histopathological features of CNS lesions proteolipid protein (PLP) and CD68 stainings were used as markers of demyelination and actived mononuclear cells, respectively

Summary

Introduction

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) resulting in a wide range of neurological symptoms including impaired sensory and/or motor function [1]. GM lesions (GML) can occur in various brain regions of MS patients, ranging from the cortex to deep gray matter structures. These GML may explain certain cognitive impairments or psychiatric problems that occur in a great number of MS patients already early in the disease [15,16]. One of the principal mediators of inflammatory processes is interleukin1b (IL-1b), which is known to play a role in MS pathogenesis It is unknown whether IL-1b is solely present in WM or in GM lesions. Using an experimental MS model, we questioned whether IL-1b and the IL-1 receptor antagonist (IL-1ra) are present in GM in addition to affected WM regions

Methods

Results

Conclusion