In-situ expression of Interleukin-18 and associated mediators in the human brain of sALS patients: Hypothesis for a role for immune-inflammatory mechanisms

doi:10.1016/j.mehy.2015.11.022

Medical Hypotheses

Volume 86, January 2016, Pages 14-17

https://doi.org/10.1016/j.mehy.2015.11.022 Get rights and content

Abstract

Recent studies reported over-expression of a cytokine (Interleukin (IL)-18) in the serum of sporadic amyotrophic lateral sclerosis (sALS) patients. Here, we report on the first-time detection of in-situ expression of activated IL-18 in the human brain in sALS patients. We also detected cerebral in-situ expression of key-molecules known to be closely related to the molecular network associated with the activation/secretion of IL-18 cytokine, namely, the receptor-interacting serine/threonine-protein kinase 3 (RIPK3 or RIP3), NOD-like receptor pyrin domain containing 3 (NLRP3)-inflammasome, and activated caspase-1.

These findings suggest and allow to hypothesize that there might be a role for this cytokine network in molecular mechanisms associated with or implicated in the physiopathology of this neurodegenerative disorder.

Section snippets

Introduction/background

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressing condition.

It is one of the severest neurodegenerative diseases that involves upper- and lower motor neurons, with typical limbs-, trunk-, and bulbar involvement, causing death usually from neurogenic muscle weakness. Many cases, besides, show or evolve with a distinctive component, namely fronto-temporal atrophy and/or dementia (FTD); a clinico-pathological spectrum of ALS/FTD has thus emerged [1], [2], and insights

The hypothesis

Growing evidence on the implication of proinflammatory cytokines in cerebral neuronal dysfunction and cell death in several neurological disorders (such as multiple sclerosis, Alzheimer’s dementia, Parkinson, and others…), together with the recent reporting of overexpression of IL-18 (a known inflammatory cytokine) in the sera of patients with sALS [13], prompted us to hypothesize that this cytokine (IL-18) could take part in physiopathological mechanisms underlying cerebral neuronal

Evaluation of the hypothesis

In order to find out if IL-18 could possibly be implicated in neural cell injury/damage particularly in the brain, it was imperative to verify and explore whether this cytokine (IL-18) and eventually related molecules, were actually present and expressed within the brain itself.

Empirical data/supportive results

To that aim, we carried-out a retrospective neuropathological study to explore sALS brains for eventual expression of IL-18 cytokine in cerebral tissue, and to see if related immune-inflammatory mediators/network were activated in the CNS of sALS patients.

We explored archived paraffin-embedded tissue-blocks from four human brains for the eventual presence of the IL-18 cytokine (in brain tissues), and we also looked for key-mediators closely related to IL-18, namely RIP3, caspase-1 and the

Discussion

Our empirical data presented herein provide first evidence on the detection of in-situ expression of activated IL-18 in the human brain in sALS patients. Interestingly, overexpression of IL-18 has been recently observed in the sera of sALS patients [13].

In this observational study, we also detected the cerebral in-situ expression/activation of key-molecules that are known to be closely related to the molecular network associated with IL-18 cytokine production/activation, namely, RIP3,

Conflict of interest statement

None.

Acknowledgements

Authors thank Mr. Abderahmane Bouysantiman and Mr. Jean-Yves Bonnet (Belgium), and Mr. Djordie Grbic and Mrs. Clémence Guiraut (Canada) for excellent technical assistance. Research-financing (HK) was provided by “Fondation Brugmann” at CHU-BRUGMANN (a non-profit University-Hospital Funding Body).

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In-situ expression of Interleukin-18 and associated mediators in the human brain of sALS patients: Hypothesis for a role for immune-inflammatory mechanisms

Abstract

Section snippets

Introduction/background

The hypothesis

Evaluation of the hypothesis

Empirical data/supportive results

Discussion

Conflict of interest statement

Acknowledgements

J Neuroimmunol

Hum Pathol

Med Hypotheses

Immunity

Mol Cell

Cortical atrophy in ALS is critically associated with neuropsychiatric and cognitive changes

Neurology

The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum

Ann Med

Basal ganglia involvement in amyotrophic lateral sclerosis

Neurology

Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis

BMC Neurol

The underestimation of familial ALS and counseling patients with sporadic ALS

Neurology

Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study

Neurology

Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration

Front Cell Neurosci

Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis

J Neurosci