HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity

ElsevierVolume 138, July 2023, 103053Journal of AutoimmunityAuthor links open overlay panel, , , , , , , , , , , Highlights•

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.

Abstract

Hepatocyte 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.

Keywords

C -myc

Cigarette smoke

CNS autoimmunity

EAE

HNF4α

Immune activation

Multiple sclerosis

Master regulator

SP1

Vitamin D

AbbreviationsaVitD3

1α,25-dihydroxyvitamin D3

CIS

clinically isolated syndromes

DEG

differentially expressed gene

EAE

experimental autoimmune encephalomyelitis

PBMC

Peripheral blood mononuclear cell

PP-MS

primary progressive MS

RR-MS

relapsing-remitting MS

SP-MS

secondary progressive MS

TFNA

transcription factor network analysis

© 2023 The Authors. Published by Elsevier Ltd.

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