Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation

Wheeler, Michael A.; Jaronen, Merja; Covacu, Ruxandra; Zandee, Stéphanie; Scalisi, Giulia; Rothhammer, Veit; Tjon, Emily; Chao, Chun‐Cheih; Kenison, Jessica E.; Blain, Manon; Rao, Vijayaraghava T.S.; Hewson, Patrick; Barroso, Andréia; Gutiérrez-Vázquez, Cristina; Prat, Alexandre; Antel, Jack P.; Hauser, Russ; Quintana, Francisco J.

doi:10.1016/j.cell.2018.12.012

Cited by 160 publications

(150 citation statements)

References 111 publications

(97 reference statements)

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“…In line with the recently discovered cross-talk between microglia and astrocytes during neuroinflammation (Rothhammer et al, 2018;Vainchtein et al, 2018;Wheeler et al, 2019), we observed that LPS injection increased astroglial GFAP reactivity. Based on the detrimental outcome of impaired astrogliosis on axon regeneration (Anderson et al, 2016), this elevated astrocytic response may contribute to restorative mechanisms that support neurological recovery.…”

Section: Discussionsupporting

confidence: 89%

Dose-Dependent Microglial and Astrocytic Responses Associated With Post-ischemic Neuroprotection After Lipopolysaccharide-Induced Sepsis-Like State in Mice

Sardari

Dzyubenko

Schmermund

et al. 2020

Front. Cell. Neurosci.

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In contrast to lipopolysaccharide (LPS)-induced preconditioning, which has repeatedly been examined in the past, the effects of post-ischemic LPS-induced sepsis, although clinically considerably more important, have not systemically been studied. We exposed mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of intraperitoneal LPS (0.1 or 1 mg/kg) which was administered 24 h postischemia. Post-ischemic glial reactivity, neuronal survival and neurological outcome were differently modulated by the higher and the lower LPS dose. Although both doses promoted neuronal survival after 72 h, the underlying mechanisms were not similar. Mice receiving 1 mg/kg LPS exhibited transient hypothermia at 1 and 3 hours post sepsis (hps), followed by reduced focal neurological deficits at 24, 48 and 72 hps. The lower dose (0.1 mg/kg) did not induce hypothermia, but reduced microglia/macrophage activation with the appearance of an anti-inflammatory CD206 positive cell phenotype in the brain parenchyma. Together, our results indicate a novel, dose-dependent modulation of microglial cells that is intricately involved in brain protection.

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Section: Discussionsupporting

confidence: 89%

Dose-Dependent Microglial and Astrocytic Responses Associated With Post-ischemic Neuroprotection After Lipopolysaccharide-Induced Sepsis-Like State in Mice

Sardari

Dzyubenko

Schmermund

et al. 2020

Front. Cell. Neurosci.

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“…Consistent with our observations, a number of recent studies have shown that microglial cells isolated from AD-like mouse models undergo important metabolic changes with the activation of the HIF pathway [65][66][67]. Furthermore, Hif1 is involved in astrocytes proinflammatory activity [68] and its activity seems to be dysregulated in association with other genes genetically linked to AD risk, suggesting that HIF-1α may be detrimental in AD pathology [66].…”

Section: Discussionsupporting

confidence: 90%

SFRP1 shapes astrocyte to microglia cross-talk in acute and chronic neuroinflammation

Rueda-Carrasco

Mateo

Borroto

et al. 2020

Preprint

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Neuroinflammation is a common feature of many neurodegenerative diseases, which often enhances neuronal loss and fosters a dysfunctional neuron-microglia-astrocyte crosstalk that, in turn, maintains microglial cells into a perniciously reactive state. The molecular components that mediates this critical communication are however non-fully explored. Here, we have asked whether Secreted-Frizzled-Related-Protein 1 (SFRP1), a multifunctional regulator of cell to cell communication, is part of the cellular crosstalk underlying neuroinflammation. We show that in mouse models of acute and chronic neuroinflammation, astrocyte-derived SFRP1 is sufficient to promote microglial activation and to enhance their response to damage, sustaining a chronic inflammatory state. SFRP1 allows the upregulation of components of Hypoxia Induced Factors-dependent inflammatory pathway and, to a much lower extent, of those downstream of the Nuclear Factor-kappaB. We thus propose that SFRP1 acts as a critical astrocyte to microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation present in several neurodegenerative diseases.Cadherin (23), whereas neutralization of its activity prevents the appearance of AD pathological traits, including glial cell activation (23). Whether SFRP1 is directly involved in the modulation of neuroinflammation remained however unexplored.By addressing this issue, here we show that Sfrp1 is a novel mediator of the astrocyte to microglia crosstalk that underlies mammalian CNS inflammation. In mice, astrocyte-derived SFRP1 is sufficient to activate microglial cells and to amplify their response to distinct acute and chronic neuroinflammatory challenges, sustaining their chronic activation. From a molecular point of view, SFRP1 allows for the full expression of down-stream targets of the transcription factors hypoxia induced factors (HIF) and, to a lesser extent, nuclear factor-kappa B (NF-κB), which are mediators of neuroinflammatory responses (24,25). Thus, neutralizing SFRP1 function may represent a strategy to counteract pernicious chronic neuroinflammation that contributes to many neurodegenerative conditions.

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“…This signal can be extracellular (e.g., cytokines, purines, aggregated proteins, and myelin debris), trans‐cellular (e.g., transmembrane adhesion molecules like ephrins or integrins), membrane bound [e.g., phosphatidylserine (Chung et al, )], as well as intracellular (e.g., aggregated proteins, nucleic acids from infecting pathogens, ions like Ca 2+ ), [see (Buffo, Rolando, & Ceruti, ; Cunningham et al, ; Kang & Hebert, ; Sofroniew, ) for review]. Interestingly, a recent study reported that astrocytes are also very sensitive to environmental pollutants (Wheeler et al, ). To sense all these molecular triggers, astrocytes are equipped with a wide range of membrane or intracellular receptors, including G Protein‐coupled receptors (like metabotropic glutamate or P2Y purinergic receptors), ionotropic receptors (e.g., P2X purinergic receptors), multimeric cytokine receptors (e.g., IL6 family receptors), Toll like receptors [although their expression by astrocytes is quite disputed (Cunningham et al, )], or tyrosine kinase receptors (e.g., Epidermal growth factor receptor), [see (Kang & Hebert, ; Verkhratsky & Nedergaard, ) for review].…”

Section: What Are the Molecular Cascades Triggered In Reactive Astrocmentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

220

180

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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.

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Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation

Cited by 160 publications

References 111 publications

Dose-Dependent Microglial and Astrocytic Responses Associated With Post-ischemic Neuroprotection After Lipopolysaccharide-Induced Sepsis-Like State in Mice

Dose-Dependent Microglial and Astrocytic Responses Associated With Post-ischemic Neuroprotection After Lipopolysaccharide-Induced Sepsis-Like State in Mice

SFRP1 shapes astrocyte to microglia cross-talk in acute and chronic neuroinflammation

Questions and (some) answers on reactive astrocytes

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