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Teriflunomide Promotes Blood-Brain Barrier Integrity by Upregulating Claudin-1 via the Wnt/β-catenin Signaling Pathway in Multiple Sclerosis

Yipeng, Z;Chen, C;Xiuqing, X;Ling, F;Yanyu, C;Xi, C;Fuhua, P;Jingqi, W;Shishi, S;Shilin, W;Wei, C;Wei, Q;

Background:The blood-brain barrier (BBB) and tight junction (TJ) proteins maintain the homeostasis of
the central nervous system (CNS). The dysfunction of BBB allows peripheral T cells infiltration into CNS
and contributes to the pathophysiology of multiple sclerosis (MS). Teriflunomide is an approved drug for
the treatment of MS by suppressing lymphocytes proliferation. However, whether teriflunomide has a
protective effect on BBB in MS is not understood.

Methods:The analysis of MS patient samples, experiment autoimmune encephalomyelitis (EAE) rat
model and BBB cell models were performed to evaluate the function of teriflunomide on BBB. The
promotion of teriflunomide on TJ proteins was assessed by qPCR, western blotting, immunofluorescence,
transendothelial electrical resistance (TEER) measurement and NaF transmittance. After RNA sequencing,
downstream signaling pathway were screened and verified using agonists, inhibitors and gene
knockdown. The protective effect of teriflunomide-regulated pathway on BBB was further examined in
EAE model.

Results:Teriflunomide restored the injured BBB in EAE model. Furthermore, teriflunomide treatment over
six months improved BBB permeability and reduced peripheral leakage of CNS proteins in MS patients.
Teriflunomide increased human brain microvascular endothelial cells (HBMECs) viability and promoted
BBB integrity in an in vitro cell model. The TJ protein claudin-1 was upregulated by teriflunomide and
responsible for the protective effect on BBB. Furthermore, RNA sequencing revealed that the Wnt
signaling pathway was affected by teriflunomide. The activation of Wnt signaling pathway increased
claudin-1 expression and reduced BBB damage in cell model and EAE rats.

Conclusion:Our study demonstrated that teriflunomide upregulated the expression of the tight junction
protein claudin-1 in endothelial cells, and promoted the integrity of BBB through Wnt signaling pathway.