Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

Deczkowska, Aleksandra; Matcovitch-Natan, Orit; Tsitsou-Kampeli, Afroditi; Ben-Hamo, Sefi; Dvir-Szternfeld, Raz; Spinrad, Amit; Singer, Oded; David, Eyal; Winter, Deborah R.; Smith, Lucas K.; Kertser, Alexander; Baruch, Kuti; Rosenzweig, Neta; Terem, Anna; Prinz, Marco; Villeda, Saul; Citri, Ami; Amit, Ido; Schwartz, Michal

doi:10.1038/s41467-017-00769-0

Cited by 185 publications

(208 citation statements)

References 71 publications

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“…In addition, increased cerebral expression is also a characteristic of physiological ageing in humans and mice (Baruch et al, 2014). In mouse studies, this was associated with activation and a proinflammatory phenotype of CNS-resident microglia (Deczkowska et al, 2017), and in vivo blockade of IFN-I signaling in aged mice improved cognitive function (Baruch et al, 2014). While these studies demonstrate that increased levels of IFN-I may be present in a wide range of neurological conditions and mediate either beneficial or detrimental effects, much work is still required to clarify their roles in specific diseases and conditions.…”

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confidence: 99%

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Wen

Viengkhou

Denyer

et al. 2018

Glia

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Type I interferons (IFN-I) are crucial for effective antimicrobial defense in the central nervous system (CNS) but also can cause severe neurological disease (termed cerebral interferonopathy) as exemplified by Aicardi-Goutières Syndrome. In the CNS, microglia and astrocytes have essential roles in host responses to infection and injury, with both cell types responding to IFN-I. While the IFN-I signaling pathways are the same in astrocytes and microglia, the extent to which the IFN-I responses of these cells differ, if at all, is unknown. Here we determined the global transcriptional responses of astrocytes and microglia to the IFN-I, IFN-α. We found that under basal conditions, each cell type has a unique gene expression pattern reflective of its developmental origin and biological function. Following stimulation with IFN-α, astrocytes and microglia also displayed a common core response that was characterized by the increased expression of genes required for pathogen detection and elimination. Compared with astrocytes, microglia had a more extensive and diverse response to IFN-α with significantly more genes with expression upregulated (282 vs. 141) and downregulated (81 vs. 3). Further validation was documented for selected IFN-I-regulated genes in a murine model of cerebral interferonopathy. In all, the findings highlight not only overlapping but importantly divergent responses to IFN-I by astrocytes versus microglia. This suggests specialized roles for these cells in host defense and in the development of cerebral interferonopathy.

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confidence: 99%

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Wen

Viengkhou

Denyer

et al. 2018

Glia

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“…IFN‐I signaling is upregulated in aged human microglia (Olah et al, ), as well as microglia from both physiological and Ercc1‐accelerated aging mouse models (Grabert et al, ; Holtman et al, ). Importantly, further profiling of the aging microglia phenotype by Deczkowska et al () showed that the microglial transcriptome of aged mice is largely defined by a response to IFN‐I, most likely a response to IFN‐β which is chronically produced at elevated levels by the choroid plexus in both aged humans and mice (Baruch et al, ). Intracerebroventricular administration of anti‐IFNAR1 neutralizing antibodies to the CSF of aged mice results in microglial transcriptomic changes inversely related to those found in the aging phenotype (Deczkowska et al, ).…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 99%

“…Similar to aged microglia, AAV-IFNβ microglia are highly reactive, have an increased number of cellular processes, and upregulate the expression of genes regulated by IFN-I (Deczkowska et al, 2017), as well as genes that are linked to cognitive decline in aging (Smith et al, 2015). The specific deletion of IFN-I signaling in microglia rescues AAV-IFNβ mice from IFN-β-driven synaptic loss and cognitive decline (Deczkowska et al, 2017). Importantly, chronic IFN-I signaling in aged mice and AAV-IFNβ mice also reduces the microglial expression of myocyte enhancer factor, Mef2C, a transcription factor which regulates the unique microglial chromatin landscape (Lavin et al, 2014) and restricts the response of microglia to inflammatory stimuli (Deczkowska et al, 2017).…”

Section: Aging and Neurodegenerative Diseasesmentioning

confidence: 99%

“…Interestingly, there is recently emerging evidence that the microglial response to IFN-I may also be a significant factor to the neuroinflammatory processes which contribute to AD pathology. In the CNS of patients with AD there are a subset of plaque-associated microglia which produce and respond to IFN-α (Akiyama, Ikeda, Katoh, McGeer, & McGeer, 1994;Yamada, Horisberger, Kawaguchi, Moroo, & Toyoda, 1994;Yamada & Yamanaka, 1995) and are hypertrophied with increased ramified processes (Akiyama et al, 1994;Mattiace, Davies, & Dickson, 1990;Walker & Lue, 2015), reminiscent of the morphological transformations observed in microglia responding to IFN-I (Akwa et al, 1998;Deczkowska et al, 2017). Consistent with these observations, transcriptomic meta-analysis of microglia from numerous mouse models of AD reveals that reactive microglia induce expression of IRGs in AD (Friedman et al, 2018).…”

Section: Aging and Neurodegenerative Diseasesmentioning

confidence: 99%

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Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

West

Viengkhou

Campbell

et al. 2019

Glia

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Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

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“…In addition, ex vivo microglia isolated from adult mice show greater secretion of both IL‐6 and TNFα (Njie et al, ). Gene ontology analysis on transcriptomic data from young and aged mice reveals that these changes are largely IFN‐dependant (Deczkowska et al, ). These changes are accompanied by morphological alterations, most notably with observations of hypertrophy (Conde and Streit, ).…”

Section: Microglia Transcriptomic Changes In Admentioning

confidence: 99%

The involvement of microglia in Alzheimer's disease: a new dog in the fight

Moore

Crack

2018

British J Pharmacology

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First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

Cited by 185 publications

References 71 publications

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

The involvement of microglia in Alzheimer's disease: a new dog in the fight

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