The circular RNA circINPP4B acts as a sponge of miR-30a to regulate Th17 cell differentiation during progression of experimental autoimmune encephalomyelitis

Circular RNAs(circRNAs)regulate gene expression and participate in various biological and pathological processes.However,little is known about the effects of specific circRNAs on T helper cell 17(Th17)differentiation and related autoimmune diseases,such as multiple sclerosis(MS).Here,using transcriptome microarray analysis at different stages of experimental autoimmune encephalomyelitis(EAE),we identified the EAE progression-related circINPP4B,which showed upregulated expression in Th17 cells from mice with EAE and during Th17 differentiation in vitro.Silencing of circINPP4B inhibited Th17 differentiation and alleviated EAE,characterized by less demyelination and Th17 infiltration in the spinal cord.Mechanistically,circINPP4B served as a sponge that directly targeted miR-30a to regulate Th17 differentiation.Furthermore,circINPP4B levels were associated with the developing phases of clinical relapsing-remitting MS patients.Our results indicate that circINPP4B plays an important role in promoting Th17 differentiation and progression of EAE by targeting miR-30a,which provides a potential diagnostic and therapeutic target for Th17-mediated MS.

MiR-3Oa-centered molecular crosstalk regulates STh17 differentiation

Recently,there has been growing interest in the specific role of Th17 cells in the pathogenesis of neuroinflammation-related degenerative diseases,including Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and multiple sclerosis(MS)[1].The Th17-mediated autoimmune response is a key determinant of these pathological outcomes.Interleukin-17(IL-17),the most important cytokine of activated Th17 cells,is considered a pivotal agent of autoimmunity because of its proinflammatory effect and migration-promoting ability.Although the specific mechanism of Th17/IL-17 is still controversial,exploring the molecular pathways of Th17/IL-17 in neurodegeneration will facilitate the identification of suitable targets to modulate these cellular processes.Th17 differentiation is directed by lineage-specific transcription factors,including RORγt and RORα,and is controlled by the coordinated activity of a series of positive and negative regulators,as well as additional signals from different cytokines to maintain and stabilize the proinflammatory features of Th17 cells[2,3].

Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.