HNF4α supports monocyte and T cell function.
•HNF4α, SP1 and c-myc are shared transcription factor network hubs among MS stages.
•Hub levels are higher in MS immune cells and regulated by environmental risk factors.
•Hubs exert non-synergic, interdependent control of CNS autoimmunity in vivo.
AbstractHepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.
KeywordsC -myc
Cigarette smoke
CNS autoimmunity
EAE
HNF4α
Immune activation
Multiple sclerosis
Master regulator
SP1
Vitamin D
AbbreviationsaVitD31α,25-dihydroxyvitamin D3
CISclinically isolated syndromes
DEGdifferentially expressed gene
EAEexperimental autoimmune encephalomyelitis
PBMCPeripheral blood mononuclear cell
PP-MSprimary progressive MS
RR-MSrelapsing-remitting MS
SP-MSsecondary progressive MS
TFNAtranscription factor network analysis
© 2023 The Authors. Published by Elsevier Ltd.
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