Neuroinflammation and the cGAS-STING pathway

Chin, Alfred C.

doi:10.1152/jn.00848.2018

Cited by 58 publications

(41 citation statements)

References 12 publications

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“…These studies suggest that PINK1 and Parkin mediated mitophagy can mitigate inflammation and autoimmune disease ( 36 , 45 , 46 ). When neurodegenerative diseases occur in the central nervous system, mitochondrial DNA can activate the innate immunity and cause neuroinflammation ( 47 ). Type I IFN contribute to the inflammatory response during normal aging and in age-related neurodegenerative disorders ( 48 – 51 ).…”

Section: Discussionmentioning

confidence: 99%

The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5

Wang

Hou

et al. 2020

Front. Immunol.

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Innate immunity is the first-line defense against antiviral or antimicrobial infection. RIG-I and MDA5, which mediate the recognition of pathogen-derived nucleic acids, are essential for production of type I interferons (IFN). Here, we identified mitochondrion depolarization inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) inhibited the response and antiviral activity of type I IFN during viral infection. Furthermore, we found that the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin mediated mitophagy, thus negatively regulating the activation of RIG-I and MDA5. Parkin directly interacted with and catalyzed the K48-linked polyubiquitination and subsequent degradation of RIG-I and MDA5. Thus, we demonstrate that Parkin limits RLR-triggered innate immunity activation, suggesting Parkin as a potential therapeutic target for the control of viral infection.

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Section: Discussionmentioning

confidence: 99%

The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5

Wang

Hou

et al. 2020

Front. Immunol.

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“…It will be interesting to observe the impact of Mϕ pyroptosis on the cGAS‐STING signaling pathway in above mentioned autoimmune diseases where NETosis plays a significant role in the immunopathogenesis. It is noteworthy that STING activation in microglia by an antiviral drug called ganciclovir decreases the microglial function and neuroinflammation in experimental autoimmune encephalomyelitis (EAE) …”

Section: Cgas‐sting Signaling In Autoinflammation and Autoimmunitymentioning

confidence: 99%

A STING to inflammation and autoimmunity

Kumar

2019

Journal of Leukocyte Biology

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Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Cyclic GMP-AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP-AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF-B-mediated generation of proinflammatory cytokines and molecules. Thus, cGAS-STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS-STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING-and TANK-binding kinase 1-mediated generation of type 1 IFNs and the activation of NF-B. The third section of the article describes the role of cGAS-STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS-STING signaling required for its regulation. Therapeutic targeting of cGAS-STING signaling could offer new ways to treat inflammatory and autoimmune diseases. K E Y W O R D S

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“…Type I IFNs are the main regulators of the host anti-viral response; in the absence of IFN signaling, mice are more susceptible to viral infection (Müller et al, 1994;Pinto et al, 2014). Following CNS injury, damageassociated molecular patterns, such as cytosolic and mitochondrial DNA, are released from injured neurons and initiate innate immune signaling that activates glia and drives secondary neuroinflammation (Walko et al, 2014;Chin, 2019;Wang et al, 2019). Microglia and astrocytes express members of the PHYIN family, which are upregulated during neurodegenerative disease (Cox et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration

et al. 2020

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DNA damage and type I interferons (IFNs) contribute to inflammatory responses after traumatic brain injury (TBI). TBI-induced activation of microglia and peripherally-derived inflammatory macrophages may lead to tissue damage and neurological deficits. Here, we investigated the role of IFN-␤ in secondary injury after TBI using a controlled cortical impact model in adult male IFN-␤-deficient (IFN-␤ Ϫ/Ϫ) mice and assessed post-traumatic neuroinflammatory responses, neuropathology, and long-term functional recovery. TBI increased expression of DNA sensors cyclic GMP-AMP synthase and stimulator of interferon genes in wild-type (WT) mice. IFN-␤ and other IFN-related and neuroinflammatory genes were also upregulated early and persistently after TBI. TBI increased expression of proinflammatory mediators in the cortex and hippocampus of WT mice, whereas levels were mitigated in IFN-␤ Ϫ/Ϫ mice. Moreover, long-term microglia activation, motor, and cognitive function impairments were decreased in IFN-␤ Ϫ/Ϫ TBI mice compared with their injured WT counterparts; improved neurological recovery was associated with reduced lesion volume and hippocampal neurodegeneration in IFN-␤ Ϫ/Ϫ mice. Continuous central administration of a neutralizing antibody to the IFN-␣/␤ receptor (IFNAR) for 3 d, beginning 30 min post-injury, reversed early cognitive impairments in TBI mice and led to transient improvements in motor function. However, anti-IFNAR treatment did not improve long-term functional recovery or decrease TBI neuropathology at 28 d post-injury. In summary, TBI induces a robust neuroinflammatory response that is associated with increased expression of IFN-␤ and other IFN-related genes. Inhibition of IFN-␤ reduces post-traumatic neuroinflammation and neurodegeneration, resulting in improved neurological recovery. Thus, IFN-␤ may be a potential therapeutic target for TBI.

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Neuroinflammation and the cGAS-STING pathway

Cited by 58 publications

References 12 publications

The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5

The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5

A STING to inflammation and autoimmunity

Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration

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