Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Steenwinckel, Juliette Van; Schang, Anne-Laure; Krishnan, Michelle L.; Degos, Vincent; Delahaye‐Duriez, Andrée; Bokobza, Cindy; Csaba, Zsolt; Verdonk, Franck; Montané, Amélie; Sigaut, Stéphanie; Hennebert, Olivier; Lebon, Sophie; Schwendimann, Leslie; Charpentier, Tifenn Le; Hassan-Abdi, Rahma; Ball, Gareth; Aljabar, Paul; Saxena, Alka; Holloway, R.; Birchmeier, Walter; Baud, Olivier; Rowitch, David H.; Miron, Véronique E.; Chrétien, Fabrice; Leconte, Claire; Besson, Valérie; Petretto, Enrico; Edwards, A. David; Hagberg, Henrik; Soussi-Yanicostas, Nadia; Fleiss, Bobbi; Gressèns, Pierre

doi:10.1093/brain/awz319

Cited by 109 publications

(189 citation statements)

References 117 publications

(176 reference statements)

Supporting

Mentioning

174

Contrasting

Order By: Relevance

“…For example, studies in vitro have shown that Wnt3a and Wnt5a can counteract LPS-induced microglia activation [75]. In contrast, in preterm-born infants and in different postnatal animal models of injured-induced neuroinflammation, downregulation of the expression of Wnt signaling components seems a prerequisite for pro-inflammatory activation of microglia [76]. SFRP1 upregulation could lead to the same net effect, inducing at least the down-regulation of the expression of Axin2 or Lef1, genes that targets and read-out of Wnt/βcatenin pathway activation.…”

Section: Discussionmentioning

confidence: 99%

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

Rueda-Carrasco

Mateo

Borroto

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Rueda-Carrasco

Mateo

Borroto

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Nonetheless, in cultured mouse microglial cells that express the Fzd4/5/7/8 receptors as well as LRP5/6, Wnt3a stimulation activated β-catenin signaling, increasing the expression of pro-inflammatory mediators such as IL6, IL12, and TNFα (Halleskog et al, 2011). However, recent findings have demonstrated that deactivation of the β-catenin signaling induced a pro-inflammatory phenotype in microglial cells (Van Steenwinckel et al, 2019). Interestingly, delivery into the brain of a Wnt agonist that mediates canonical pathway activation specifically in microglia by using a microglia-specific targeting nano-carrier, microglial cell pro-inflammatory phenotype was attenuated (Van Steenwinckel et al, 2019).…”

Section: Implication In Immunitymentioning

confidence: 97%

“…However, recent findings have demonstrated that deactivation of the β-catenin signaling induced a pro-inflammatory phenotype in microglial cells (Van Steenwinckel et al, 2019). Interestingly, delivery into the brain of a Wnt agonist that mediates canonical pathway activation specifically in microglia by using a microglia-specific targeting nano-carrier, microglial cell pro-inflammatory phenotype was attenuated (Van Steenwinckel et al, 2019). More investigations are required to clearly address the complex role of Wnt pathway in regulating microglial cell activation.…”

Section: Implication In Immunitymentioning

confidence: 99%

Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries

2020

View full text Add to dashboard Cite

The Wnt pathway, which comprises the canonical and non-canonical pathways, is an evolutionarily conserved mechanism that regulates crucial biological aspects throughout the development and adulthood. Emergence and patterning of the nervous and vascular systems are intimately coordinated, a process in which Wnt pathway plays particularly important roles. In the brain, Wnt ligands activate a cellspecific surface receptor complex to induce intracellular signaling cascades regulating neurogenesis, synaptogenesis, neuronal plasticity, synaptic plasticity, angiogenesis, vascular stabilization, and inflammation. The Wnt pathway is tightly regulated in the adult brain to maintain neurovascular functions. Historically, research in neuroscience has emphasized essentially on investigating the pathway in neurodegenerative disorders. Nonetheless, emerging findings have demonstrated that the pathway is deregulated in vascular-and traumatic-mediated brain injuries. These findings are suggesting that the pathway constitutes a promising target for the development of novel therapeutic protective and restorative interventions. Yet, targeting a complex multifunctional signal transduction pathway remains a major challenge. The review aims to summarize the current knowledge regarding the implication of Wnt pathway in the pathobiology of ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI). Furthermore, the review will present the strategies used so far to manipulate the pathway for therapeutic purposes as to highlight potential future directions.

show abstract

“…Microglial activation is almost ubiquitously reported across forms of perinatal brain injury, and a causal role for these processes in injury has been demonstrated across paradigms (117,118). Conversely, a neuroprotective role for microglia is also shown in other experimental settings (119,120).…”

Section: Reactive Gliosismentioning

confidence: 99%

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

Ross-Munro¹,

Kwa

Kreiner³

et al. 2020

Front. Neurol.

Self Cite

View full text Add to dashboard Cite

Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation.

show abstract

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Cited by 109 publications

References 117 publications

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

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

Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

Contact Info

Product

Resources

About