Natural Diterpenoid Oridonin Ameliorates Experimental Autoimmune Neuritis by Promoting Anti-inflammatory Macrophages Through Blocking Notch Pathway.

Lu Xu,Lei Li,Chen-Yang Zhang,Zhi-Yuan Zhang,Hermann Schluesener

doi:10.3389/fnins.2019.00272

Abstract

The diterpenoid compound, Oridonin, extracted from the Chinese herb, Rabdosia rubescens, possesses multiple biological activities and properties. Oridonin exhibited efficient anti-inflammatory activity by inducing a switch in macrophage polarization to the anti-inflammatory phenotype through inhibition of the Notch pathway in our in vitro study; therefore, its potential therapeutic effects were further investigated in the animal model of human Guillain-Barré syndrome (GBS) and other polyneuropathies – experimental autoimmune neuritis (EAN). Either preventive or therapeutic treatments with Oridonin greatly attenuated disease peak severity, suppressed paraparesis, shortened disease duration, and even delayed EAN onset. Progression of neuropathic pain, demyelination, inflammatory cellular accumulations, and inflammatory cytokines in peripheral nerves were significantly attenuated. Meanwhile, accumulation of immune cells in the spinal roots and microglial activation in the lumbar spinal cord were also reduced. Interestingly, Oridonin treatment significantly increased the proportion of anti-inflammatory macrophages and made them locally dominant among all infiltrated macrophages in the peripheral nerves. The down-regulation of local Notch pathway proteins, together with our in vitro results indicated their possible involvement. Taken together, our results demonstrated that Oridonin effectively suppressed EAN by attenuating local inflammatory reaction and increasing the proportion of immune regulating macrophages in the peripheral nerves, possibly through blockage of the Notch pathway, which suggests Oridonin as a potential therapeutic candidate for human GBS and neuropathies.

Highlights

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy; the world’s leading cause of acute autoimmune neuromuscular paralysis, caused by an autoimmune attack on the peripheral nervous system (PNS) (Willison, 2005; Kuwabara and Yuki, 2013)
As the anti-inflammatory phenotype of macrophages can attenuate the inflammatory response and promote tissue repair, we first investigated whether Oridonin could inhibit the inflammatory response of the macrophages cell line, RAW, and the primary peritoneal macrophages by favoring a switch of macrophages from classically activated inflammatory into the anti-inflammatory phenotype in vitro
The expression levels of IL-1β, tumor necrosis factor (TNF)-α, and IL-10 from the primary macrophages were detected with the ELISA assay

Summary

Introduction

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy; the world’s leading cause of acute autoimmune neuromuscular paralysis, caused by an autoimmune attack on the peripheral nervous system (PNS) (Willison, 2005; Kuwabara and Yuki, 2013). Experimental autoimmune neuritis (EAN), an autoantigen-specific, T cellmediated animal model for demyelinating inflammatory diseases of the PNS, is broadly accepted and used to study pathogenesis, pathological changes, and potential therapeutic approaches for human polyneuropathies like GBS, by mirroring many of their neurological, electrophysiological, immunological, and pathological features (Hughes and Cornblath, 2005). Infiltrating macrophages cause tissue damage by secretion of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF)α, and these are responsible for demyelination and axon loss as well (Kiefer et al, 2001). Anti-inflammatory macrophages are considered to control inflammatory reactions and are responsible for tissue repair; they are characterized by the high expression of anti-inflammatory molecules such as IL-10 and arginase-I (Mosser and Edwards, 2008; Ricardo et al, 2008). Y. et al, 2010; Han et al, 2016a,b)

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Conclusion