Astrocyte Regulation of CNS Inflammation and Remyelination

Abstract

Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…To date, little is known about the role of astrocytes in Krabbe disease, where the majority of studies have mainly been focused on the role oligodendrocytes in this illness. Altered astrocytic function has gained recognition as a major contributing factor to a growing number of neurological disorders (Claycomb et al, 2013) and the belief that astrocytic dysfunction significantly contributes to the development of inflammation in the CNS has gained traction in the past number of years (Sharma et al, 2010). In addition, the immunomodulatory functions of astrocytes are now being shown to actively participate in the pathogenesis of a number of demyelinating disorders (Sharma et al, 2010).…”

“…This indicates that demyelination in Krabbe disease may not be solely attributed to oligodendrocyte dysfunction and that given correct environmental support these twi/twi oligodendrocytes may function normally. Thus, astrocytic reactivity in Krabbe disease may not represent a secondary response to demyelination, but may possibly be a primary response to psychosine and in turn astrocytes may significantly contribute to the pathogenesis of Krabbe disease (Claycomb et al, 2013). In our current study, we obtained data that demonstrated a direct effect of psychosine on astrocyte cell death and attenuation by pFTY720.…”

“…Inflammatory processes have been implicated in the pathogenesis of Krabbe disease and the expression of pro-inflammatory cytokines have been reported in the twi/twi mouse brain (Claycomb et al, 2013;LeVine and Brown, 1997). However, the mechanism governing psychosine-mediated cell toxicity and the direct role of proinflammatory cytokines in the degeneration of astrocytes and/or oligodendrocytes is still not fully understood.…”

Lipopolysaccharide-Induced Apoptosis of Astrocytes: Therapeutic Intervention by Minocycline

“…Activated astrocytes proliferate and produce a variety of inflammatory mediators such as nitric oxide (NO), TNF-a, etc. that contribute to the pathogenesis of various neurodegenerative diseases (Sofroniew and Vinters 2010;Claycomb et al 2013). Although there are reports indicating NO-mediated apoptosis of astrocytes in rat primary astrocyte culture exposed to a combination of LPS and inflammatory cytokines but not by either alone (Suk et al 2001;Caruso et al 2007;Quintas et al 2014).…”

The Physiological Basis of Cervical Facet-Mediated Persistent Pain: Basic Science and Clinical Challenges

“…Like other chronic pain conditions, spinal astrocytes are activated for at least 14 days after painful facet stretch. 16,17 Mechanical injury to the facet capsule also regulates the production of inflammatory mediators, including proinflammatory cytokines and neurotrophins, in the facet joint itself, as well as in the DRG. 46,48,53,69 Because peripheral inflammation increases hyperexcitability and substance P in DRG neurons, along with pain production, 96,110 recent studies have begun to elucidate the molecular mechanisms by which peripheral inflammation contributes to central sensitization in the context of facet-mediated pain.…”