NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis

Abstract

BackgroundBrain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown.MethodsCre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation.ResultsWe show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model.ConclusionsThese findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Reactivity and Increased Proliferation of NG2 Cells Following Central Nervous System Infection With Theiler’s Murine Encephalomyelitis Virus

“…NG2 cells express a wide array of Ca 2+ channels and receptors that regulate diverse aspects of NG2 cell morphology and function, including immune signaling, process dynamics, cell migration, intercellular communication, and release of trophic and secreted factors (25). Reactive NG2 cells displayed characteristic thick and ramified processes, reinforcing the possibility that NG2 cells, like other glia, likely undergo altered gene expression and physiological changes that coincide with the observed morphological changes following CNS infection (24,25,38,39).…”

“…However, a growing body of evidence indicates much broader and more complex roles for NG2 cells in nervous system function and disease and has led to their classification as the fourth major glial cell type (17)(18)(19)(20). NG2 cells receive both inhibitory and excitatory synaptic inputs and express a distinguishing array of ion channels, receptors, and an immunoproteasome, uniquely priming them to monitor and respond to changes in the neural environment (19,(21)(22)(23)(24)(25).…”

“…Several studies have identified immune antigen-presentation on NG2 cells in response to neurological insult or injury, suggesting NG2 cells may play a role in the inflammatory milieu contributing to seizures following TMEV-infection(21,27,32,47,48). Conversley, NG2 cells have also been shown to supress neruoinflammation and microglial activation thorugh TGF-β signaling(24). These diametric findings suggest that reactive NG2 glia may assume immune-promoting or immune-suppressing roles in a context-specific manner.…”

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

“…The authors concluded that reduced NG2-derived trophic support via hepatocyte growth factor was responsible for this loss of neurons ( 181 ). Furthermore, NG2-derived transforming growth factor β2 (TGF-β2) signaling to TGF-β receptor 2 on microglia was shown to be a key regulator of microglial CX3CR1-mediated immune responses, and deficiency of this signaling axis via NG2 ablation led to neuronal loss and inflammation ( 182 ). Hence, the ability of NG2 glia to respond to neuronal inputs, as well as retaining a high proliferative potential in the human brain, makes this cell type another interesting glial cell in the context of TSC.…”

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler’s murine encephalomyelitis virus

“…However, a growing body of evidence indicates much broader and more complex roles for NG2 cells in nervous system function and disease and has led to their classification as the fourth major glial cell type [19][20][21][22]. NG2 cells receive both inhibitory and excitatory synaptic inputs and express a distinguishing array of ion channels, receptors, and an immunoproteasome, uniquely priming them to monitor and respond to changes in the neural environment [21,[23][24][25][26][27].…”