IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3

Han Liu,Yanpeng Yuan,Jing Yang,Rui Zhang,Yanlin Wang,Xueke Yang,Yuming Xu,Huangui Xiong

doi:10.3389/fncel.2021.679413

Abstract

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. IL-17 level is significantly increased in inflammatory conditions of the CNS, including but not limited to post-stroke and multiple sclerosis. IL-17 has been detected direct toxicity on oligodendrocyte (Ol) lineage cells and inhibition on oligodendrocyte progenitor cell (OPC) differentiation, and thus promotes myelin damage. The cellular mechanism of IL-17 in CNS inflammatory diseases remains obscure. Voltage-gated K+ (Kv) channel 1.3 is the predominant Kv channel in Ol and potentially involved in Ol function and cell cycle regulation. Kv1.3 of T cells involves in immunomodulation of inflammatory progression, but the role of Ol Kv1.3 in inflammation-related pathogenesis has not been fully investigated. We hypothesized that IL-17 induces myelin injury through Kv1.3 activation. To test the hypothesis, we studied the involvement of OPC/Ol Kv1.3 in IL-17-induced Ol/myelin injury in vitro and in vivo. Kv1.3 currents and channel expression gradually decreased during the OPC development. Application of IL-17 to OPC culture increased Kv1.3 expression, leading to a decrease of AKT activation, inhibition of proliferation and myelin basic protein reduction, which were prevented by a specific Kv1.3 blocker 5-(4-phenoxybutoxy) psoralen. IL-17-caused myelin injury was validated in LPC-induced demyelination mouse model, particularly in corpus callosum, which was also mitigated by aforementioned Kv1.3 antagonist. IL-17 altered Kv1.3 expression and resultant inhibitory effects on OPC proliferation and differentiation may by interrupting AKT phosphorylating activation. Taken together, our results suggested that IL-17 impairs remyelination and promotes myelin damage by Kv1.3-mediated Ol/myelin injury. Thus, blockade of Kv1.3 as a potential therapeutic strategy for inflammatory CNS disease may partially attribute to the direct protection on OPC proliferation and differentiation other than immunomodulation.

Highlights

In the central nervous system (CNS), neuronal axons are myelinated with oligodendrocytes (Ols), and damage of such a myelin sheath is a striking pathological feature of white matter damage in many inflammation-related diseases, including stroke (Oksala et al, 2009), Alzheimer disease (Nasrabady et al, 2018), and in particular multiple sclerosis (MS), which is a disseminated sclerosis in CNS affecting millions of people worldwide
Previous studies reported that Kv1.3 on T lymphocytes and microglial cells play a key role in pathophysiological processes in inflammatory brains; we explored whether oligodendrocyte progenitor cell (OPC)/Ol Kv1.3 was directly involved in inflammation-related myelin injury
We demonstrated that Kv1.3 blockade effectively promoted OPC proliferation and differentiation through activation of AKT signaling, leading to protection of myelin from Interleukin 17 (IL-17)– and LPC- induced myelin damage in vitro and in vivo, which is beneficial to remyelination in neurological disorders with demyelination

Summary

Introduction

In the central nervous system (CNS), neuronal axons are myelinated with oligodendrocytes (Ols), and damage of such a myelin sheath is a striking pathological feature of white matter damage in many inflammation-related diseases, including stroke (Oksala et al, 2009), Alzheimer disease (Nasrabady et al, 2018), and in particular multiple sclerosis (MS), which is a disseminated sclerosis in CNS affecting millions of people worldwide. While the mechanisms underlying MS pathogenesis are not fully understood, it is widely accepted that myelin sheath destruction induced by autoimmune response is most likely the cause. In MS, the immune system attacks myelin sheath leading to demyelination and impairs remyelination by retardation or inhibition of the myelin-producing cells to form myelin sheath after demyelination (Boulanger and Messier, 2014). Remyelination requires Ol progenitor cell (OPC) proliferation and migration to the lesion sites, where they differentiate, eventually to mature Ols and wrap neuronal axons to form myelin sheath. Current therapies targeting at suppression of overactive immune cells, such as lymphocytes, have some promising effects in retarding disease progression (Hauser et al, 2013), there is no effective way to stimulate and promote axonal remyelination once a demyelinated lesion has occurred

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