The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis

Abstract

Neuroinflammation is the coordinated response of the central nervous system (CNS) to threats to its integrity posed by a variety of conditions, including autoimmunity, pathogens and trauma. Activated astrocytes, in concert with other cellular elements of the CNS and immune system, are important players in the modulation of the neuroinflammatory response. During neurological disease, they produce and respond to cellular signals that often lead to dichotomous processes, which can promote further damage or contribute to repair. This occurs also in multiple sclerosis (MS), where astrocytes are now recognized as key components of its immunopathology. Evidence supporting this role has emerged not only from studies in MS patients, but also from animal models, among which the experimental autoimmune encephalomyelitis (EAE) model has proved especially instrumental. Based on this premise, the purpose of the present review is to summarize the current knowledge of astrocyte behavior in MS and EAE. Following a brief description of the pathological characteristics of the two diseases and the main functional roles of astrocytes in CNS physiology, we will delve into the specific responses of this cell population, analyzing MS and EAE in parallel. We will define the temporal and anatomical profile of astroglial activation, then focus on key processes they participate in. These include: 1) production and response to soluble mediators (e.g. cytokines and chemokines), 2) regulation of oxidative stress, and 3) maintenance of BBB integrity and function. Finally, we will review the state of the art on the available methods to measure astroglial activation in vivo in MS patients, and how this could be exploited to optimize diagnosis, prognosis and treatment decisions. Ultimately, we believe that integrating the knowledge obtained from studies in MS and EAE may help not only better understand the pathophysiology of MS, but also uncover new signals to be targeted for therapeutic intervention.

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…Astrocytes play a major role in the induction and modification of brain inflammation, which is summarized and discussed in a number of excellent recent review articles (Brambilla, 2019;Ludwin, Rao, Moore, & Antel, 2016;Ponath, Park, & Pitt, 2018;Soung & Klein, 2018;Wheeler & Quintana, 2019). For this reason, only few aspects will be addressed here, which go beyond the issues covered in detail in these articles.…”

“…As a prominent source of cytokines, chemokines and other inflammatory mediators they are instrumental both in the propagation as well as in the downregulation of inflammatory responses in the brain. Due to their strategic location at the blood brain interface they are important for blood brain barrier function and in particular in controlling the spread of inflammatory cells from the perivascular space into the parenchyma (Brambilla, 2019). They further promote T-cell proliferation and expansion by antigen presentation via the expression of MHC Class I and Class II molecules or costimulatory molecules (Höftberger et al, 2004).…”

Astrocytes in Pathogenesis of Multiple Sclerosis and Potential Translation into Clinic

“…Astrocytes play a pivotal role in formation and maintenance of the blood-brain barrier (BBB), a highly selective physical border that separates the CNS parenchyma from blood circulation through extension of processes of an end-foot membrane that surrounds CNS capillaries [31]. The end-foot membrane contains the channel protein aquaporin-4 (AQP4) and the gap junction protein connexin 43 (Cx43) that allow astrocytes to tightly regulate the selective exchange of water-soluble molecules and ions with blood vessels [32]. In a healthy state, astrocytes constitutively secrete low basal levels of the anti-inflammatory cytokines including transforming growth factor-β (TGF-β) [33] and interleukin-10 (IL-10) [34] to maintain a stable noninflammatory environment.…”

Neuroinflammation, the thread connecting neurological disease

“…These points are especially evident in MS and its widely adopted animal model experimental autoimmune encephalomyelitis (EAE), discussed by Brambilla [7]. In this review article, Brambilla focused on the contribution of astrocytes to the neuroinflammatory response in MS and EAE, from their temporal profile of activation during disease onset and evolution, to the soluble mediators they release and the cellular processes they affect.…”

“…While our understanding of the neuroinflammatory mechanisms is in constant evolution and remodeling, there is little doubt that neuroinflammation is a prominent feature of virtually every neurological/neurodegenerative disorder, the common thread that connects traumatic, neurodegenerative, and psychiatric CNS pathologies. The purpose of the review cluster "Neuroinflammatory mechanisms in neurodegenerative disorders" published in this issue of Acta Neuropathologica is to provide an overview of the state of the art on neuroinflammation in the context of a broad spectrum of neurological disorders, form traumatic (spinal cord injury (SCI) [5], and traumatic brain injury (TBI) [6]), to chronic neurodegenerative (multiple sclerosis (MS) [7], and amyotrophic lateral sclerosis (ALS) [8]) and ischemic multifactorial (stroke) [9]. The authors paid particular attention to address emerging evidence of the contrasting roles that specific molecules and cell types play in the pathophysiology of each disease.…”