Human microglia and astrocytes express cGAS-STING viral sensing components

Jeffries, Austin M; Marriott, Ian

doi:10.1016/j.neulet.2017.08.039

Cited by 49 publications

(37 citation statements)

References 17 publications

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“…Consistent with these findings in mice, we have shown that cytosolic administration of a dsDNA ligand can phosphorylate IRF3 and induce IFN-β mRNA expression in primary human microglia and astrocytes (Jeffries and Marriott, 2017), and we have demonstrated that such responses are largely dependent on cGAS expression (Jeffries and Marriott, 2017;Jeffries et al, 2020). Furthermore, we showed that ISG expression is lower in cGAS deficient human microglia both at rest and following infection with HSV-1 (Jeffries et al, 2020).…”

Section: Cgas/stingsupporting

confidence: 84%

“…Interestingly, while they observed neither constitutive nor IFN-β-inducible expression of cGAS in murine astrocytes, siRNA-mediated cGAS knockdown decreased IFN-β activity in both microglia and astrocytes following exposure to exogenous dsDNA (Cox et al, 2015). Further support for the presence of cGAS in glia has since been provided by our demonstration that primary human microglia and astrocytes both constitutively express cGAS protein and its downstream adaptor molecule STING (Jeffries and Marriott, 2017).…”

Section: Cgas/stingmentioning

confidence: 95%

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Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Jeffries

Marriott

2020

Front. Cell. Infect. Microbiol.

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Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.

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Section: Cgas/stingsupporting

confidence: 84%

Section: Cgas/stingmentioning

confidence: 95%

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Jeffries

Marriott

2020

Front. Cell. Infect. Microbiol.

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“…Upon binding dsDNA, cGAS converts ATP and GTP to 2′-5′cGAMP, a cyclic di-nucleotide second messenger, which subsequently binds the ER-membrane bound protein, stimulator of interferon genes (STING), leading to the recruitment of TBK1 and activation of the IRF3-interferon axis (Chen and others 2016). Both cGAS and STING are expressed in human microglia and astrocytes (Jeffries and Marriott 2017), and in vivo studies have begun to establish the importance of cGAS-STING pathway both in CNS infection and in sterile inflammation. For example, cGAS or STING deficient mice are highly susceptible to herpes simplex encephalitis (HSE), abolishing microglial type 1 interferons and the ability of astrocytes to upregulate TLR3 (Reinert and others 2016).…”

Section: Astrocytes As Innate Immune Cellsmentioning

confidence: 99%

Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

2018

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Astrocytes are the most numerous cell type in the brain and perform several essential functions in supporting neuronal metabolism and actively participating in neural circuit and behavioural function. They also have essential roles as innate immune cells in responding to local neuropathology and the manner in which they respond to brain injury and degeneration is the subject of increasing attention in neuroscience. Although activated astrocytes have long been thought of as a relatively homogenous population, which alter their phenotype in a relatively stereotyped way upon CNS injury, the last decade has revealed substantial heterogeneity in the basal state and significant heterogeneity of phenotype during reactive astrocytosis. Thus phenotypic diversity occurs at two distinct levels: that determined by regionality and development and that determined by temporally dynamic changes to the environment of astrocytes during pathology. These inflammatory and pathological states shape the phenotype of these cells, with different consequences for destruction or recovery of the local tissue and thus elucidating these phenotypic changes has significant therapeutic implications. In this review, we will focus on the phenotypic heterogeneity of astrocytes in health and disease and their propensity to change that phenotype upon subsequent stimuli.

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“…Similar to other myeloid immune cells such as macrophages, microglia express an array of cell surface, endosomal and cytoplasmic PRRs, allowing them to rapidly respond to the presence of PAMPs and DAMPs in the extracellular milieu and within the cytosol. In addition to the well-studied Toll-like and nucleotide-binding oligomerization domain (NOD)-like families of receptors (TLR and NLR, respectively), more recent work has demonstrated the ability of these sentinel cells to functionally express molecules that serve as cytosolic sensors for foreign and/or damaged nucleic acid motifs that include DNA-dependent activator of interferon-regulatory factors (DAI), retinoic acid-inducible gene (RIG)-like receptors (RLR) and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS; Bowman et al, 2003 ; Liu et al, 2010 ; Furr et al, 2011 ; Crill et al, 2015 ; Jeffries and Marriott, 2017 ). Interestingly, non-leukocytic CNS cells, including astrocytes, can also express such innate immune sensing molecules although, in contrast to microglia, such cells appear to constitutively express fewer PRR types and expression levels (Bsibsi et al, 2002 , 2006 ).…”

Section: Introductionmentioning

confidence: 99%

The Interleukin-10 Family of Cytokines and Their Role in the CNS

Burmeister

Marriott

2018

Front. Cell. Neurosci.

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161

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Resident cells of the central nervous system (CNS) play an important role in detecting insults and initiating protective or sometimes detrimental host immunity. At peripheral sites, immune responses follow a biphasic course with the rapid, but transient, production of inflammatory mediators giving way to the delayed release of factors that promote resolution and repair. Within the CNS, it is well known that glial cells contribute to the onset and progression of neuroinflammation, but it is only now becoming apparent that microglia and astrocytes also play an important role in producing and responding to immunosuppressive factors that serve to limit the detrimental effects of such responses. Interleukin-10 (IL-10) is generally considered to be the quintessential immunosuppressive cytokine, and its ability to resolve inflammation and promote wound repair at peripheral sites is well documented. In the present review article, we discuss the evidence for the production of IL-10 by glia, and describe the ability of CNS cells, including microglia and astrocytes, to respond to this suppressive factor. Furthermore, we review the literature for the expression of other members of the IL-10 cytokine family, IL-19, IL-20, IL-22 and IL-24, within the brain, and discuss the evidence of a role for these poorly understood cytokines in the regulation of infectious and sterile neuroinflammation. In concert, the available data indicate that glia can produce IL-10 and the related cytokines IL-19 and IL-24 in a delayed manner, and these cytokines can limit glial inflammatory responses and/or provide protection against CNS insult. However, the roles of other IL-10 family members within the CNS remain unclear, with IL-20 appearing to act as a pro-inflammatory factor, while IL-22 may play a protective role in some instances and a detrimental role in others, perhaps reflecting the pleiotropic nature of this cytokine family. What is clear is that our current understanding of the role of IL-10 and related cytokines within the CNS is limited at best, and further research is required to define the actions of this understudied family in inflammatory brain disorders.

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Human microglia and astrocytes express cGAS-STING viral sensing components

Cited by 49 publications

References 17 publications

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

The Interleukin-10 Family of Cytokines and Their Role in the CNS

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