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Multiple Sclerosis
Microglia and Chitotriosidase in Multiple Sclerosis
a report by
Stefano Sotgiu,
1
Salvatore Musumeci,
2
Silvia Marconi
3
and Bruno Bonetti
3
1. Section of Neurology, Department of Neurosciences and Maternal–Infant Sciences, University of Sassari; 2. Institute of Biomolecular Chemistry,
Italian National Research Council, Sassari; 3. Section of Neurology, Department of Neurological Sciences and Vision, University of Verona
Initial biochemical investigations led to the unexpected discovery that Given its peculiar immune ‘privilege’, healthy central nervous system
plasma samples of patients with Gaucher disease (GD), a lysosomal (CNS) status is tightly regulated and maintained at a low functional level
storage disease, had a several hundred-fold elevated ability to hydrolyse in order to prevent immune-mediated damage from occurring. Among
chitin, a polymer of beta 1,4-linked N-acetylglucosamine that is largely brain cells, microglia and a few other cell types such as astrocytes
diffuse in nature.
1
Later, the same investigators observed that lipid-laden represent components of the innate immune system that promptly
activated macrophages accumulating in GD tissues were able to secrete activate a complex immune cascade soon after specific or unspecific
exceedingly high levels of an enzyme able to cleave chitin and artificial stimuli – either ischaemic–oxidative or inflammatory – face the brain.
chitotrioside substrates, therefore named chitotriosidase (Chit).
2,3
The Microglia are the resident macrophages in the CNS. They exert important
measurement of plasma Chit activity has now also found an application functions such as phagocytosis of cellular debris and/or neuronal signal
in the clinical monitoring of patients with Fabry disease.
4
processing when activated through communications with neurons,
immune cells and other glial cells.
20–22
Activation of microglia occurs in
Chit is a member of the mammalian chitinase family. It is mainly most pathological processes. This activation is accompanied by changes
synthesised by activated macrophages and also by immature neutrophils
5
in morphology, upregulation of immune surface antigens and production
as a 50kDa protein, proteolitically cleaved and predominantly secreted. Its of cytotoxic or neurotrophic molecules.
20,23,24
natural substrate, chitin, is known for being an integral part of an
arthropod’s exoskeleton.
6–9
Its content is variable within species and is Despite the fact that chitin is absent in humans, Chit has been found to
reported to account for up to 20% of the fungal cell wall.
10,11
So far, no be elevated in some brain diseases, as described below. However,
definitive mammalian chitin synthetase has been documented, although chitin-like substances have recently been found to accumulate within
a pathogenic role of this oligosaccharide in vertebrates has been the brain in certain circumstances. Several lines of evidence exist that
reported. Chitin is utilised in the enhancement of the inflammatory roles implicate impaired glucose metabolism in several CNS diseases.
25–27
It is
of macrophages and neutrophils
11,12
and, in such instances, may also known that brain hypoperfusion and several inflammatory conditions
modulate the cerebral microglial activation documented in neuro- lead to increased glucose metabolism, which in turn strongly increases
inflammatory and neurodegenerative diseases.
13,14
hexosamine pathway activity in endothelial cells, leading to synthesis of
glucosamine polymers.
28,29
Glucosamine has various physiological
An important question arises when considering that chitin is absent in properties: it inhibits pro-inflammatory cytokines from antigen-
humans. However, the fact that the Chit gene is present and conserved in presenting cells (APCs), suppresses T-cell response by interfering with
rodents and primates
15
argues in favour of a biological role of this enzyme. functions of APC and shows a direct inhibitory effect on CD3-driven
T-cell proliferation.
30,31
Glucosamine administration in the animal model
Chit, Chitin and the Central Nervous System of multiple sclerosis (MS), known as experimental autoimmune
In pathological conditions Chit has achieved an increasingly important encephalomyelitis (EAE), significantly reduces macrophage infiltration
role as a marker of some neurological diseases,
16
perhaps by virtue of the within the inflamed brain and reduces microglial activation and
peculiar immune condition that characterises the brain. Nonetheless, production of nitric oxide (NO) and inflammatory cytokines, such as
physiological conditions such as ageing have also been found to correlate interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor
with a progressive increase of plasmatic Chit activity.
17,18
This might (TNF)-α, resulting in resistance to acute EAE.
31
However, glucosamine
suggest that the innate immune system is involved in protecting the polymers are also the building blocks of chitin and chito-
healthy human organism from cell damage that occurs during ageing, saccharides.
28,32–34
Thus, the markedly augmented glucose metabolism
perhaps linked to oxidative processes.
19
that occurs during inflammation or hypoperfusion within the brain
could induce increased formation of chitin-like substances.
33,34
Stefano Sotgiu is an Associate Professor of Neurology at the
University of Sassari, where he holds teaching courses on
Chit in Stroke
clinical neurology for medical students, nurses and residents. It is now very well established that after an acute brain ischaemia, early
His research focuses on the immunopathogenesis and
activation of microglia and endothelial cells and their transcription of
neurovirology of multiple sclerosis. He received his diploma
in medicine magna cum laude in 1988, his specialism in
TNF-α and IL-6 are able to induce a cascade of inflammatory pathways
neurologymagna cum laude in 1992 and his post-doctorate
that transforms local endothelia into a pro-thrombotic state and allows
qualification in neuroimmunology at the Max Planck
Institute in 1993–1994.
peripheral mono- and poly-morphonuclear cytotoxic chemoattraction
into the lesion site.
35,36
This early event correlates with the worsening
E: stefanos@uniss.it
of the cerebral damage, as a clear relationship between the extent of
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