Role of proteoglycans in neuro-inflammation and central nervous system fibrosis

doi:10.1016/j.matbio.2018.01.015

Matrix Biology

Volumes 68–69, August 2018, Pages 589-601

https://doi.org/10.1016/j.matbio.2018.01.015 Get rights and content

Highlights

•
Proteoglycans participate in the inflammatory response in the central nervous system, by maintaining functionality of the extracellular matrix and contributing to the the lesion scar.
•
The formation of scar tissue restrains the site of injury but also creates an environment that prevents axon regeneration and tissue repair.
•
Inflammation and fibrosis contribute to the pathogenesis of chronic neurodegenerative diseases.

Abstract

Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans.

Introduction

Tissue fibrosis, or scar formation, is an essential part of wound healing and therefore a common consequence of tissue damage [1]. In contrast to the pathology of epithelium and stroma damage in the peripheral organs, the central nervous system (CNS) is unique in the sense that fibrogenic cells are restricted to vascular (pericytes) and meningeal areas. The blood-brain barrier (BBB) plays a key role in maintaining homeostasis of the CNS and enabling communication with the systemic system. In acute CNS injuries, the disruption of the BBB is often the primary event that triggers the fibrotic response, while in chronic neurodegenerative conditions, the BBB damage can occur after tissue injury and is often related to chronic inflammation and/or reactive microglia [2]. When the BBB is damaged, hematogenous cells infiltrate into the neural tissue, activating the fibrotic response [3]. This leads to deposition of thrombin and fibrinogen; as well as destruction of the integrity in the extracellular matrix (ECM). The inflammatory reaction leads to local neural degeneration, formation of a cystic cavity and activation of glial cells. As a consequence, two types of scarring tissue are formed: the glial scar and the fibrotic scar. Although the scar tissue serves to restore the BBB and limit the damage to the site of injury, it also inhibits the healing process by producing inhibitory molecules and by forming a physical and biochemical barrier that prevents regenerating axons [4] and neural progenitor cells [5] to migrate to the site of injury.

Apart from the acute injuries, several chronic diseases in the CNS, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and age-related neurodegeneration, are associated with inflammation. The recurrent chronic inflammation leads to formation of fibrotic scar or plaque, which is often an irreversible neurodegenerative condition, affecting the functions of ECM and neurons.

The ECM in the central nervous system is unique. Unlike the peripheral organs, the ECM forms a lattice-like structure composed of hyaluronic acid and proteoglycans (PG), mainly chondroitin sulfate proteoglycans (CSPG). Proteoglycans are key regulators of neural plasticity, which is modulated by ADAMTSs [6]. Heparan sulfate proteoglycans (HSPG) have been recognized to play multiple roles in inflammatory processes, including sequestration of pro-inflammatory molecules and regulation of the leukocyte recruitment from blood to the injury site. The negatively charged heparan sulfate (HS) polysaccharide chains interact with an array of inflammatory chemokines, which are stored in the ECM, controlling the functions of these inflammatory factors under neuro-inflammation [7]. The function of HSPGs is modulated by the activity of heparanase that is an endo-glucuronidase specifically cleaving HS. Elevated heparanase expression has been found associated with several inflammatory disorders [8]. While a majority of reports point to a pro-inflammatory activity for heparanase, we have shown that overexpression of heparanase attenuates neuro-inflammation [9]. Considering the distinctive structure of ECM and BBB in the CNS, it is interesting to find out the controversial effects of heparanase expression in neuro-inflammation, e.g. whether HSPG is of similar importance for blood-borne immune cell infiltration through the brain capillaries.

Section snippets

The formation of the glial scar

The formation of the glial scar is also called reactive gliosis. After injury of the CNS, astrocytes, microglia and glial progenitor cells are activated, which leads to a major anatomical rearrangement (Fig. 1). Astrocytes become hypertrophic and start to express glial fibrillary acidic protein (GFAP) [12], as well as other extracellular matrix (ECM) proteins [13]. These reactive astrocytes are responsible for forming a dense scar, which serves to restore the BBB and confines the inflammatory

The formation of the fibrotic scar

The fibrotic scar is primarily composed of activated myofibroblasts, which are responsible for the secretion of ECM, mainly collagen type IV, fibronectin and laminin (Fig. 1) [44]. The origin of these fibroblasts remains controversial, since the CNS parenchyma does not have a resident fibroblast population. Possibly they derive from several cell populations, including migration of fibroblasts from the meningeal regions and transformation from pericytes [45]. The inflammatory response after

Contributions of proteoglycans and neuro-inflammation to Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder affecting the cognitive ability of patients. One of the characteristics is the formation of ‘plaques’ - excess fibrous tissue - in the brain. Histopathological analysis of brain tissue from AD patients shows the typical deposition of extracellular amyloid beta (Aβ) peptides, along with several other extracellular molecules, including serum amyloid P, apolipoprotein E and GAGs (mainly HSPG) [53]. Aβ is derived from cleavage of amyloid-β

Reactive gliosis and proteoglycans in multiple sclerosis

Multiple sclerosis is a chronic inflammatory and demyelinating disease that results in plaques of primary demyelination and diffuse neurodegeneration in the brain. The pathological mechanisms that drive neurodegeneration in MS are poorly understood, but it is generally accepted that it is a result of an inflammatory response. Inflammatory cells, mainly auto-reactive CD4+ T-lymphocytes, infiltrate into the CNS parenchyma, where they secrete factors that contribute to the development and

Activated astrocytes in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterised by the gradual and progressive loss of dopaminergic neurons in the substantia nigra of the brain. Neuro-inflammatory responses in PD consist of the activation of glia cells and the recruitment of T-cells from the peripheral immune system. This leads to an increased expression and release of pro-inflammatory cytokines and chemokines, as well as an increased expression of enzymes involved in the production of reactive oxygen

Inflammation and senescence in the aging brain

The aging process leads to functional and structural changes in the human brain. Increased expression of GFAP and vimentin has been the most common changes observed in astrocytes with aging, indicating the presence of reactive gliosis [65]. Aging affects many functional brain characteristics regulated by astrocytes, such as metabolism and synaptic plasticity. Astrocytes also play a major role in maintaining the structure of the BBB and it is generally accepted that aging increases BBB

Future research questions and directions

Several pathological conditions of the CNS are accompanied by inflammation and disruption of the BBB. The rapid post-injury fibrotic response serves to seal this breach in the BBB and contain the site of injury. However, reactive astrocytes and fibroblasts also express axon-repelling molecules and the deposition of ECM leads to an accumulation of proteoglycans, some of which are known to inhibit neural outgrowth. This dual role of the lesion scar makes is particularly difficult to prevent and

Acknowledgements

The financial supports from the Swedish Cancer Foundation (2015-02595) to F. Heindryckx (CAN2013/1273 & CAN2017/518) and to J.-P Li (CAN150815) and from the Swedish Research Council are gratefully acknowledged.

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ReviewRole of proteoglycans in neuro-inflammation and central nervous system fibrosis

Highlights

Abstract

Introduction

Section snippets

The formation of the glial scar

The formation of the fibrotic scar

Contributions of proteoglycans and neuro-inflammation to Alzheimer's disease

Reactive gliosis and proteoglycans in multiple sclerosis

Activated astrocytes in Parkinson's disease

Inflammation and senescence in the aging brain

Future research questions and directions

Acknowledgements

Matrix Biol.

Brain Behav. Immun.

Cell

Matrix Biol.

Matrix Biol.

Matrix Biol.

Neuroscience

Trends Neurosci.

Matrix Biol.

Exp. Neurol.

World Neurosurg.

Neurosci. Lett.

Int. J. Dev. Neurosci.

Mol. Cell. Neurosci.

Am. J. Pathol.

J. Neurosci. Methods

Brain Res. Bull.

Neurobiol. Aging

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Lancet Neurol.

Exp. Neurol.

Neuroscience

Am. J. Pathol.

J. Biol. Chem.

J. Neuroimmunol.

Neuroimage Clin.

Eur. J. Pharmacol.

Exp. Neurol.

Neurosci. Res.

J. Neuroimmunol.

J. Neurol. Sci.

Mol. Immunol.

J. Neurol. Sci.

Roles of chondroitin sulfate and dermatan sulfate in the formation of a lesion scar and axonal regeneration after traumatic injury of the mouse brain

J. Neurotrauma

Endogenous neural progenitor cells in the repair of the injured spinal cord

Neural Regen. Res.

Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain

Acta Neuropathol.

Proteoglycans and neuronal migration in the cerebral cortex during development and disease

Front. Neurosci.

Astrocytes as a source for extracellular matrix molecules and cytokines

Front. Pharmacol.

Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury

J. Neuroinflammation

Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage

J. Neurosci.

Neurocan is upregulated in injured brain and in cytokine-treated astrocytes

J. Neurosci.

NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury

BMC Neurol.

Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells

J. Neurosci.

Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis

J. Neurosci. Res.

The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth

J. Cell Biol.

The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury

J. Neurosci.

Decorin treatment of spinal cord injury

Neural Regen. Res.

Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries

Eur. J. Neurosci.

Review
Role of proteoglycans in neuro-inflammation and central nervous system fibrosis