Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Abstract

Microglia of the developing brain have unique functional properties but how their activation states is regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain with multiple models of neuroinflammation-mediated injury and primary human microglia we found that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive an oligodendrocyte-injurious microglial phenotype. We validated in a cohort of preterm born infants that genomic variation in the WNT pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a BBB penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits.Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury

“…Overall the data in this study on neuropathological findings and neuroinflammatory events associated with neuroinflammation alone was similar to what we have published previously (Favrais et al, 2011;Krishnan et al, 2017;Schang et al, 2014;Shiow et al, 2017;Van Steenwinckel et al, 2018).…”

“…We wish to highlight that the predominate reason for this is that previous post-mortem data from our lab and from others of preterm born infant neuropathology shows that oligodendrocyte cell death is not a major contributor to injury, but that microgliosis and hypomyelination are observed (Billiards et al, 2008;Verney et al, 2010;Verney et al, 2012). Our animal model captures these clinical features, of very limited cell death, microgliosis and eventual hypomyelination (Favrais et al, 2011;Schang et al, 2014;Van Steenwinckel et al, 2018).…”

“…Use of P1-P5 mice to model the preterm infant brain is supported by comparative studies of brain growth and oligodendrocyte maturation (Back et al, 2001;Dean et al, 2011;Dobbing and Sands, 1979) and reviewed in (Semple et al, 2013). Full descriptions of the model including systemic and central inflammatory response and neuropathology are available within these references (Favrais et al, 2011;Krishnan et al, 2017;Schang et al, 2014;Shiow et al, 2017;Van Steenwinckel et al, 2018).…”

Lipopolysaccharide‐induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

“…To further support the potential validity of targeting fission as a therapeutic strategy, we tested the ability of Mdivi‐1 to modify microglial activity in vivo. We used a paradigm of systemically driven neuroinflammation, wherein an IP injection of the inflammatory agent interleukin‐1β induces a highly complex neuroinflammatory reaction involving microglia (Krishnan et al, ; Van Steenwinckel et al, ). Supporting our in vitro data mdivi‐1 was able to reduce the expression of genes associated with classically pro‐inflammatory genes and the anti‐inflammatory activation state, which is associated with the in vivo inflammatory reaction.…”

“…We used a well‐characterized paradigm of systemic inflammation driven neuroinflammation (Favrais et al, ; Krishnan et al, ; Van Steenwinckel et al, ), which is known to have effects on brain development and behavior consistent with those reported in infants and children born preterm (Ball et al, ; Raju, Buist, Blaisdell, Moxey‐Mims, & Saigal, ). Experimental protocols were approved by the institutional guidelines of the Institute National de la Santé et de la Recherche Scientifique (Inserm) France.…”