Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

Cunningham, Colm; Dunne, Aisling; López-Rodríguez, Ana Belén

doi:10.1177/1073858418809941

Cited by 60 publications

(62 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Reactive astrocytes are the usual suspects in many diseases, but they are now considered by many, as beneficial partners for neurons, as illustrated in Table . An overview of the literature shows that depending on the strategy employed to modulate reactive astrocytes (e.g., pharmacological or genetic approaches, targeting of astrocyte proteins or signaling pathways, ablation of astrocytes), the outcomes vary (Ben Haim, Carrillo‐de Sauvage, et al, ; Cunningham et al, ). Of course, the disease studied and its model itself (e.g., transgenic versus knock‐in, in vivo versus in vitro, species) will influence how astrocyte reaction will play out.…”

Section: Do Reactive Astrocytes Do Good Things?mentioning

confidence: 99%

“…But, this dual classification may be quite restrictive to define other potential types of reactive astrocytes existing in the complex world of brain diseases (Cunningham, Dunne, & Lopez-Rodriguez, 2018). Indeed, many intermediate molecular profiles were observed after treatment of immunopanned astrocytes with different molecules, not only A1 or A2 .…”

Section: Reversibilitymentioning

confidence: 99%

See 1 more Smart Citation

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

232

180

View full text Add to dashboard Cite

Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

show abstract

Section: Do Reactive Astrocytes Do Good Things?mentioning

confidence: 99%

Section: Reversibilitymentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

232

180

View full text Add to dashboard Cite

show abstract

“…Astrocytes are cells of ectodermal origin and have some specificity in their responses to inflammatory stimuli [15][16][17][18]. These cells fulfill an important role as innate immune cells in the brain [19]. As a regulator of brain inflammation, astrocytes can release various immune and inflammatory mediators, such as pro-and anti-inflammatory cytokines/chemokines and oxylipins, which may subsequently exert neurotoxic or neuroprotective effects [6,12,15].…”

Section: Introductionmentioning

confidence: 99%

Oxylipin Profiles as Functional Characteristics of Acute Inflammatory Responses in Astrocytes Pre-Treated with IL-4, IL-10, or LPS

Chistyakov

Gavrish

Goriainov

et al. 2020

IJMS

View full text Add to dashboard Cite

Functional phenotypes, which cells can acquire depending on the microenvironment, are currently the focus of investigations into new anti-inflammatory therapeutic approaches. Glial cells, microglia, and astrocytes are major participants in neuroinflammation, but their roles differ, as microglia are cells of mesodermal origin, while astrocytes are cells of ectodermal origin. The inflammatory phenotype of cells can be modulated by ω-6- and ω-3-polyunsaturated fatty acid-derived oxylipins, although data on changes in oxylipin profiles in different cell adaptations to pro- and anti-inflammatory stimuli are scarce. Our study aimed to compare UPLC-MS/MS-measured oxylipin profiles in various rat astrocyte adaptation states. We used cells treated for 24 h with lipopolysaccharide (LPS) for classical pro-inflammatory adaptation and with interleukin 4 (IL-4) or 10 (IL-10) for alternative anti-inflammatory adaptation, with the resulting phenotypes characterized by quantitative real-time PCR (RT-PCR). We also tested long-term, low-concentration LPS treatment (endotoxin treatment) as a model of astrocyte adaptations. The functional response of astrocytes was estimated by acute (4 h) LPS-induced cell reactivity, measured by gene expression markers and oxylipin synthesis. We discovered that, as well as gene markers, oxylipin profiles can serve as markers of pro- (A1-like) or anti-inflammatory (A2-like) adaptations. We observed predominant involvement of ω-6 polyunsaturated fatty acid (PUFA) and the cyclooxygenase branch for classical (LPS) pro-inflammatory adaptations and ω-3 PUFA and the lipoxygenase branch for alternative (IL-4) anti-inflammatory adaptations. Treatment with IL-4, but not IL-10, primes the ability of astrocytes to activate the innate immunity signaling pathways in response to LPS. Endotoxin-treated astrocytes provide an alternative anti-inflammatory adaptation, which makes cells less sensitive to acute LPS stimulation than the IL-4 induced adaptation. Taken together, the data reveal that oxylipin profiles associate with different states of polarization to generate a pro-inflammatory or anti-inflammatory phenotype. This association manifests itself both in native cells and in their responses to a pro-inflammatory stimulus.

show abstract

“…Astrocytes are regionally heterogeneous in morphology, gene expression, and function during physiological and pathological conditions (74, 75). Since the iP is readily induced by IFNγ, which is present at all stages of MS (34, 76), and astrocytes are in and around MS lesions and respond to IFNγ, we further explored heterogenous regulation of the astrocyte iP between the brainstem and spinal cord driven by IFNγ.…”

Section: Resultsmentioning

confidence: 99%

“…These findings broaden our understanding of astrocyte heterogeneity in the CNS. Although regional heterogeneity of astrocytes in neurophysiologic functions (18, 19, 105) and in many disease models (106-108), including EAE (75, 109, 110), has been appreciated, there are no studies to date that have described a regional role for the iP in the CNS. However, a regional difference in Type I IFN signaling in astrocytes has been described (111).…”

Section: Discussionmentioning

confidence: 99%

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Sinyuk

et al. 2019

Preprint

View full text Add to dashboard Cite

17In early autoimmune neuroinflammation, interferon (IFN)g and its upregulation of the 18 immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNg has 19 protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated 20 that IFNg signaling in regional astrocytes induces the iP and protects the CNS during 21 autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem 22 lesions, which correlated with a decrease in oxidative stress. In vitro, IFNg stimulation enhanced 23 iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and 24 poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was 25 abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal 26 model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated 27 disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice 28 with astrocyte-specific loss of the IFNg receptor exhibited worsened chronic EAE associated with 29 reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein 30 accumulation in astrocytes. Taken together, our data reveal a protective role for IFNg in chronic 31 neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity. 32 33 34 Multiple sclerosis (MS) is the most common chronic inflammatory and 35 neurodegenerative disease of the central nervous system (CNS) (1). During the 36 pathogenesis of MS, there is immune cell infiltration, demyelination, and reactive gliosis 37within CNS lesions in multiple regions (2). Relapsing-remitting MS (RRMS) is a subtype 38 that affects approximately 85% of patients and is characterized by episodic periods of 39 neurological dysfunction, often associated with inflammation, followed by partial or 40 complete recovery. A significant proportion of these patients go on to develop secondary 41 progressive MS (SPMS), during which they have fewer remissions and increasing 42 atrophy, correlating with progressive disability (3, 4). Primary progressive (PPMS) a third 43 subtype of MS, affects approximately 15% of patients and is associated with continuous, 44 progressive loss of neurological function after initial diagnosis, without periods of 45 remission (5, 6). Of note, it is thought that the pathology associated with RRMS has a 46 relatively significant inflammatory component, while in SPMS and PPMS, inflammation is 47 an animal model of MS, astrocytes are known to exhibit regional heterogeneity in gene 58 expression and response to inflammation (17)(18)(19). Indeed, ablation of astrocytes following 59 several types of CNS injury leads to sustained inflammation, impaired repair, and 60 increased neurodegeneration (20-29), suggesting that a diverse astrocytic response is 61 critical in healthy tissue preservation and support, minimizing CNS bystander damage 62 during...

show abstract

Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

Cited by 60 publications

References 140 publications

Questions and (some) answers on reactive astrocytes

Questions and (some) answers on reactive astrocytes

Oxylipin Profiles as Functional Characteristics of Acute Inflammatory Responses in Astrocytes Pre-Treated with IL-4, IL-10, or LPS

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Contact Info

Product

Resources

About