Anemoside A3 ameliorates experimental autoimmune encephalomyelitis by modulating T helper 17 cell response.

Fanny C F Ip,Guangmiao Fu,Nancy Y Ip,Jessica Y H Li,Peiran Sun,Yu Pong Ng,Tom H Cheung,Wen-Cai Ye,Terry C T Or,Hossam M Ashour

doi:10.1371/journal.pone.0182069

Abstract

Anemoside A3 (AA3) is a natural triterpenoid glycoside isolated from the root of Pulsatilla chinensis (Bunge) Regel. We previously showed that AA3 exhibits cognitive-enhancing and neuroprotective properties. In the present study, we demonstrated that AA3 modulates inflammatory responses by regulating prostaglandin E receptor 4 signaling. Because prostaglandin E receptor 4 is involved in the pathophysiology of experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), we assessed the beneficial effect of AA3 in EAE mice. AA3 treatment significantly reduced clinical severity and inflammatory infiltrates in the spinal cord of EAE mice. In vitro studies revealed that AA3 inhibited the T cell response toward the encephalitogenic epitope of myelin oligodendrocyte glycoprotein (MOG). AA3 significantly downregulated the expressions of certain Th1 and Th17 cytokines in activated T cells re-stimulated by MOG. Moreover, AA3 inhibited the activation of STAT4 and STAT3, which are the transcription factors pivotal for Th1 and Th17 lineage differentiation, respectively, in activated T cells. Pharmacological analysis further suggested that AA3 reduced Th17 cell differentiation and expansion. In conclusion, AA3 exerts an immunomodulatory effect in EAE, demonstrating its potential as a therapeutic agent for MS in humans.

Highlights

Multiple sclerosis (MS) is a chronic neurological disease with characteristic pathological findings of episodic neurologic dysfunction, perivascular inflammation, demyelination, and axon degeneration in the central nervous system (CNS)
Following stimulation with prostaglandin E2 (PGE2), the level of cyclic adenosine monophosphate (cAMP) increased in THP-1 cells, which was inhibited by Anemoside A3 (AA3) with a half maximal inhibitory concentration (IC50) of 22.4 ± 5.8 μM (Fig 1A)
The present study is the first to demonstrate that AA3 modulates the PGE2–EP4 signaling pathway

Summary

Introduction

Multiple sclerosis (MS) is a chronic neurological disease with characteristic pathological findings of episodic neurologic dysfunction, perivascular inflammation, demyelination, and axon degeneration in the central nervous system (CNS). Histological investigation of the white matter from patients with MS shows that the demyelinating plaques are distributed within the optic nerves, brainstem, cerebellum, and spinal cord [4]. These demyelinating plaques can subsequently lead to axonal damage and contribute to disability [2, 3, 5]. Mounting evidence indicates that prostaglandin E2 (PGE2) signaling profoundly influences the pattern of CD4+ T cell responses in neuroinflammatory disorders including MS [7, 10, 11]. PGE2–EP4 signaling is a promising target for the development of therapeutics for MS

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Conclusion