IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity

Kocur, Magdalena; Schneider, Reiner; Pulm, Ann-Kathrin; Bauer, Jens; Kropp, Sonja; Gliem, Michael; Ingwersen, Jens; Goebels, Norbert; Alferink, Judith; Prozorovski, Timour; Aktaş, Orhan; Scheu, Stefanie

doi:10.1186/s40478-015-0192-4

Cited by 91 publications

(76 citation statements)

References 58 publications

(70 reference statements)

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“…Microglia is verified to play an important role in the process of remyelination (Voss et al, 2012; Miron et al, 2013; Doring et al, 2015; Lampron et al, 2015). Accumulating evidence suggests that microglia is associated with the clearance and phagocytosis of degraded and collapsed myelin debris, existence of which is detrimental to OPC proliferation and remyelination (Kotter et al, 2005, 2006; Ruckh et al, 2012; Kocur et al, 2015). Studies also found that microglia, especially M2 phenotype, are positively related to the recruitment of OPCs and their differentiation into mature oligodendrocytes, as well as myelin formation (Miron et al, 2013; Wang et al, 2015; Marteyn et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

et al. 2017

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Promoting remyelination is crucial for patients with demyelinating diseases including multiple sclerosis. However, it is still a circuitous conundrum finding a practical remyelinating therapy. Electroacupuncture (EA), originating from traditional Chinese medicine (TCM), has been widely used to treat CNS diseases all over the world, but the role of EA in demyelinating diseases is barely known. In this study, we examined the remyelinating properties and mechanisms of EA in cuprizone-induced demyelinating model, a CNS demyelinating murine model of multiple sclerosis. By feeding C57BL/6 mice with chow containing 0.2% cuprizone for 5 weeks, we successfully induce demyelination as proved by weight change, beam test, pole test, histomorphology, and Western Blot. EA treatment significantly improves the neurobehavioral performance at week 7 (2 weeks after withdrawing cuprizone chow). RNA-seq and RT-PCR results reveal up-regulated expression of myelin-related genes, and the expression of myelin associated protein (MBP, CNPase, and O4) are also increased after EA treatment, indicating therapeutic effect of EA on cuprizone model. It is widely acknowledged that microglia exert phagocytic effect on degraded myelin debris and clear these detrimental debris, which is a necessary process for subsequent remyelination. We found the remyelinating effect of EA is associated with enhanced clearance of degraded myelin debris as detected by dMBP staining and red oil O staining. Our further studies suggest that more microglia assemble in demyelinating area (corpus callosum) during the process of EA treatment, and cells inside corpus callosum are mostly in a plump, ameboid, and phagocytic shape, quite different from the ramified cells outside corpus callosum. RNA-seq result also unravels that most genes relating to positive regulation of phagocytosis (GO:0050766) are up-regulated, indicating enhanced phagocytic process after EA treatment. During the process of myelin debris clearance, microglia tend to change their phenotype toward M2 phenotype. Thus, we also probed into the phenotype of microglia in our study. Immuno-staining results show increased expression of CD206 and Arg1, and the ratio of CD206/CD16/32 are also higher in EA group. In conclusion, these results demonstrate for the first time that EA enhances myelin debris removal from activated microglia after demyelination, and promotes remyelination.

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Section: Introductionmentioning

confidence: 99%

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

et al. 2017

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“…The same deletion in B or T cells had no effect on disease severity (Prinz et al 2008). Further depicting the role of IFN-β in microglia, Kocur et al (2015) used IFN-β-florescent reporter mice to show that microglia are the major producers of IFN-β at the peak stage of EAE and accomplish IFN-β-induced clearance of myelin debris.…”

Section: Ifn-βmentioning

confidence: 99%

Microglial Phenotypes and Functions in Multiple Sclerosis

O’Loughlin

Madore

Lassmann

et al. 2018

Cold Spring Harb Perspect Med

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“…also found that IFN signaling in myeloid cells, but not in lymphocytes or neural cells, is required for protection against EAE. In agreement with this, Kocur et al . showed that microglia produce IFN‐β at the peak of EAE, and that IFN‐β enhances the capacity of microglia to clear myelin debris in an autocrine fashion.…”

Section: Endogenous Type I Ifn In Msmentioning

confidence: 57%

Endogenous type I interferons and their regulators in multiple sclerosis

Miyazaki

Niino

2017

Clinical & Exp Neuroim

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. In the past few decades, several disease-modifying drugs including interferon (IFN)-b have become available for treating MS. IFN-b belongs to the type I IFN family, and thus is an endogenous molecule whose primary role is thought to be host defense against viruses. In addition, type I IFN are constitutively produced at low amounts and involved in the homeostasis of various tissues. In contrast, it is suggested that type I IFN play a pathogenic role in other autoimmune diseases, such as lupus. Several lines of evidence from studies using MS samples and animal models suggest the protective role of endogenous type I IFN in MS. Correspondingly, MS patients with a higher endogenous type I IFN signature show lower disease activity. Paradoxically, these patients have been shown to respond poorly to IFN-b therapy. In addition, an animal model with a defective regulatory mechanism in type I IFN signaling has been shown to develop augmented central nervous system autoimmunity, suggesting that type I IFN responses need to be appropriately regulated in MS. Multiple endogenous molecules participate in the regulation of type I IFN responses, but their roles in MS have not been studied extensively. Further study delineating the role of endogenous type I IFN and their regulatory mechanisms in MS should enhance our understanding of the disease, and could lead to improvements in the therapeutic effects of IFN-b in MS.

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IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity

Cited by 91 publications

References 58 publications

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance

Microglial Phenotypes and Functions in Multiple Sclerosis

Endogenous type I interferons and their regulators in multiple sclerosis

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