Microglial immune checkpoint mechanisms

Deczkowska, Aleksandra; Amit, Ido; Schwartz, Michal

doi:10.1038/s41593-018-0145-x

Cited by 133 publications

(117 citation statements)

References 98 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, among the set of downregulated genes in Phf15 KO cells at baseline and 6 h after LPS stimulation is myocyte enhancer factor 2C (Mef2C). MEF2C is an important checkpoint inhibitor that restrains microglial activation in response to proinflammatory insults and is lost in brain aging via IFN-I mediated downregulation [63,65] . Thus, an increase in Phf15 expression in microglia during healthy aging could putatively work to counteract not only microglial activation but increased IFN-I in the aged brain as well.…”

Section: Discussionmentioning

confidence: 99%

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

Muroy¹,

Timblin²,

Preininger³

et al. 2020

View full text Add to dashboard Cite

How to cite this article: Muroy SE, Timblin GA, Preininger MK, Cedillo P, Saijo K. Phf15 -a novel transcriptional repressor regulating inflammation in mouse microglia cell line. Neuroimmunol Neuroinflammation 2020;7:166-82. http://dx. AbstractAim: Excessive microglial inflammation has emerged as a key player in mediating the effects of aging and neurodegeneration on brain dysfunction. Thus, there is great interest in discovering transcriptional repressors that can control this process. We aimed to examine whether Phf15 -one of the top differentially expressed genes in microglia during aging in humans -could regulate transcription of proinflammatory mediators in microglia. Methods:Real-time quantitative PCR was used to assess Phf15 mRNA expression in mouse brain during aging. Lossof-function [short hairpin RNA (shRNA) -mediated knockdown (KD) and CRISPR/Cas9-mediated knockout (KO) of Phf15 ] and gain-of-function [retroviral overexpression (OE) of murine Phf15 cDNA] studies in a murine microglial cell line (SIM-A9) followed by immune activation with lipopolysaccharide were used to determine the effect of Phf15 on proinflammatory factor (Tnfα , IL-1β , and Nos2 ) mRNA expression. RNA sequencing was used to determine global transcriptional changes after Phf15 knockout under basal conditions and after lipopolysaccharide stimulation.Results: Phf15 expression increases in mouse brain during aging, similar to humans. KD, KO, and OE studies determined that Phf15 represses mRNA expression levels of proinflammatory mediators such as Tnfα , IL-1β , and Nos2 . Global transcriptional changes after Phf15 KO showed that Phf15 specifically represses genes related to the antiviral (type I interferon) response and cytokine production in microglia. Conclusion:We provide the first evidence that Phf15 is an important transcriptional repressor of microglial inflammation, regulating the antiviral response and proinflammatory cytokine production. Importantly, Phf15 regulates both basal and signal-dependent activation and controls the magnitude and duration of the microglial inflammatory response.

show abstract

Section: Discussionmentioning

confidence: 99%

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

Muroy¹,

Timblin²,

Preininger³

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Microglia are remarkably long‐lived cells (Fuger et al, ; Reu et al, ) which can be primed by inflammatory stimuli over the lifetime of the cell to become hyper‐responsive to insult or injury. In addition, expression of restraining factors, which limit microglial activation, is reduced in the aging CNS (reviewed in (Deczkowska, Amit, & Schwartz, )). As a result, the aged CNS has elevated production of inflammatory factors, including IL‐6 (Burton et al, ; Burton & Johnson, ) and IFN‐I (Baruch et al, ).…”

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

confidence: 99%

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

West

Viengkhou

Campbell

et al. 2019

Glia

View full text Add to dashboard Cite

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.

show abstract

“…Several of the immunosuppresive pathways evident in GBM are in place in the normal brain. In response to TGF-b, microglia suppress immunological activity and promote normal microglial functions such as synaptic pruning and neuronal growth support (42).…”

Section: Multiple Mechanisms Of Tumour-mediated Downregulation Of Nkmentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Nsengimana

Reilly

et al. 2019

Preprint

View full text Add to dashboard Cite

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To better understand this problem we used a combination of NK cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment.In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of TGF-b mediated inhibition. This NK cell inhibition is accompanied by expression of mutiple immune checkpoint molecules on T cells. Single cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognised by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more likely benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

show abstract

Microglial immune checkpoint mechanisms

Cited by 133 publications

References 98 publications

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

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

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Contact Info

Product

Resources

About