Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression

Nazmi, Arshed; Field, Robert H.; Griffin, Éadaoin W.; Haugh, Orla; Hennessy, Edel; Cox, Dónal J.; Reis, Renata Rodrigues dos; Tortorelli, Lucas Silva; Murray, Carol; López-Rodríguez, Ana Belén; Jin, Lei; Lavelle, Ed C.; Dunne, Aisling; Cunningham, Colm

doi:10.1002/glia.23592

Cited by 101 publications

(96 citation statements)

References 81 publications

(135 reference statements)

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“…In the central nervous system (CNS), microglia is considered to be the main source of cGAS-STING-dependent IFN expression (197). In neurodegenerative diseases, levels of the marker of microglia activation-cluster of differentiation 68 (CD68), and pro-inflammatory cytokines are increased (198). A significant feature of Parkinson's disease (PD) is the neuronal loss of cerebral nuclei (especially dopaminergic neurons in the substantianigra).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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“…Interestingly, prion‐infected mice show exacerbated neurodegeneration and accelerated disease progression when peripherally challenged with the IFN‐I inducer poly I:C, implicating the actions of IFN‐I in prion disease pathogenesis (Field, Campion, Warren, Murray, & Cunningham, ). In line with this notion, it has been recently demonstrated by Nazmi et al () that in prion disease, microglia are the primary source of IFN‐I in the CNS and have a robust IFN‐I signature, which is dependent on stimulator of IFN genes (STING)‐mediated IFN‐I signaling. IFN‐I signaling is also required for upregulated expression of phagocytic and proteolytic genes in microglia and, remarkably, Ifnar1 deletion in mice with prion disease ameliorates neurodegeneration in the thalamus, delays late‐stage functional impairments, and significantly increases survival time (Nazmi et al, ).…”

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

confidence: 81%

“…In line with this notion, it has been recently demonstrated by Nazmi et al (2019) that in prion disease, microglia are the primary source of IFN-I in the CNS and have a robust IFN-I signature, which is dependent on stimulator of IFN genes (STING)-mediated IFN-I signaling. IFN-I signaling is also required for upregulated expression of phagocytic and proteolytic genes in microglia and, remarkably, Ifnar1 deletion in mice with prion disease ameliorates neurodegeneration in the thalamus, delays late-stage functional impairments, and significantly increases survival time (Nazmi et al, 2019). These findings indicate that the response of microglia to IFN-I triggers these cells to mediate synaptic and neuronal loss and contribute to disease progression in chronic neurodegeneration.…”

Section: Aging and Neurodegenerative Diseasesmentioning

confidence: 82%

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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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“…Type-I interferons (IFNs) are pleiotropic cytokines that have been implicated in neuropathologies, including Gaucher disease [ 1 ], Aicardi–Goutieres syndrome [ 2 ] and a model of prion disease [ 3 ]. Supporting this, several reports have identified a detrimental role for type-I IFNs in animal models of Alzheimer’s disease (AD) [ 4 , 5 ], Parkinson’s disease (PD) [ 6 ] and traumatic brain injury (TBI) [ 7 ], with elevated expression of type-I IFNs found in post-mortem human AD, PD and TBI brains [ 4 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

STING-Mediated Autophagy Is Protective against H2O2-Induced Cell Death

Abdullah

Mobilio

Crack

et al. 2020

IJMS

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Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the H2O2-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING−/− MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in H2O2-treated WT cells as compared to STING−/− cells. STING−/− cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following H2O2 treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against H2O2-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.

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Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression

Cited by 101 publications

References 81 publications

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

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

STING-Mediated Autophagy Is Protective against H2O2-Induced Cell Death

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