Aβ Induces Neuroinflammation and Microglial M1 Polarization via cGAS-STING-IFITM3 Signaling Pathway in BV-2 Cells

Wu, Zheng; Tang, Wei; Ibrahim, Fatima Elzahra E. M.; Chen, Xuejing; Yan, Hongting; Tao, Chunmei; Wang, Zhiming; Guo, Yunchu; Fu, Yu; Wang, Qi; Ge, Yakun

doi:10.1007/s11064-023-03945-5

Cited by 13 publications

(5 citation statements)

References 39 publications

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“…Aside from our own study [2], others have also compared Alzheimer's disease and COVID-19 transcriptomes and found shared dysregulations in innate immune pathways, including IFITM and OAS family genes both in neuropathological studies and murine models [18,73]. IFITM3 is of particular note as its expression has been shown to be modulated by cGAS-STING, a pathway that is critical for SARS-CoV-2 infection [74] as it is for resilience against tau [62] and Aβ [75] induced neuroinflammation-with IFITM3 itself being an amyloidogenic gamma secretase modulator [14]. Notably, the cGAS-STING3 axis is responsive to both cytosolic DNA regardless of its origin (i.e., intrinsic or xenobiotic) and to extrinsic tau fibrils [13] and Aβ seeds [75].…”

Section: Type I Interferon Signaling As Common Ground Between Covid-1...mentioning

confidence: 71%

“…IFITM3 is of particular note as its expression has been shown to be modulated by cGAS-STING, a pathway that is critical for SARS-CoV-2 infection [74] as it is for resilience against tau [62] and Aβ [75] induced neuroinflammation-with IFITM3 itself being an amyloidogenic gamma secretase modulator [14]. Notably, the cGAS-STING3 axis is responsive to both cytosolic DNA regardless of its origin (i.e., intrinsic or xenobiotic) and to extrinsic tau fibrils [13] and Aβ seeds [75]. Downstream cGAS-STING-mediated activation of the [NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome under sterile and non-sterile triggers [76,77], however, may exacerbate both tau and Aβ pathology and its propagation, in part via IFN-I signaling relayed from microglia to neurons [78].…”

Section: Type I Interferon Signaling As Common Ground Between Covid-1...mentioning

confidence: 99%

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SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

Vavougios,

Mavridis,

Doskas

et al. 2024

CIMB

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Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer’s. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer’s disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer’s disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene–Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer’s disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer’s disease pathology, whereas nine genes were associated with increased risk for Alzheimer’s disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer’s disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted.

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Section: Type I Interferon Signaling As Common Ground Between Covid-1...mentioning

confidence: 71%

Section: Type I Interferon Signaling As Common Ground Between Covid-1...mentioning

confidence: 99%

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

Vavougios,

Mavridis,

Doskas

et al. 2024

CIMB

View full text Add to dashboard Cite

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“…Following an initial pathogen-induced stimulation, endogenous DAMPs (such as nucleic acids and proteopathic seeds) produced by neuronal damage would fuel second-order IFN-I dysregulation by a sterile inflammatory response ( Rubartelli, 2014 ). Notably, interferon stimulated genes such as IFITMs and OASs, as we and other have reported ( Magusali et al, 2021 ; Vavougios et al, 2021a , b ) are linked to nucleic acid surveillance mechanisms ( Magusali et al, 2021 ; Vavougios et al, 2022b ) such as the OAS antiviral response and cGAS-STING, where Αβ and tau pathobiology converge with IFN-I dysregulation and inflammasome activation ( Magusali et al, 2021 ; Udeochu et al, 2023 ; Wu et al, 2023 ). Focusing on IFN-I modulation and restoration of canonical signaling may thus represent an important axis of therapeutics that is currently underexplored.…”

Section: Discussionmentioning

confidence: 83%

“…Excessive exposure to the secretion of type I interferon by the microglia either in vitro or in vivo can lead to derangement of functional neuronal maturation ( Hattori et al, 2020 ). Notably, tau and beta amyloid have been shown to stimulate microglia and upregulate IFN-I via cGAS-STING, a pathway that is furthermore linked to IFITM3 ( Jin et al, 2021 ; Wu et al, 2023 ) further linking innate immunity and Alzheimer’s disease.…”

Section: Are Sars-cov-2-introduced Perturbations In Type I Interferon...mentioning

confidence: 99%

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer’s disease

Vavougios,

Tseriotis,

Liampas

et al. 2024

Front. Hum. Neurosci.

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COVID-19’s effects on the human brain reveal a multifactorial impact on cognition and the potential to inflict lasting neuronal damage. Type I interferon signaling, a pathway that represents our defense against pathogens, is primarily affected by COVID-19. Type I interferon signaling, however, is known to mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis and neuronal damage. In previous studies, we proposed a model of outside-in dysregulation of tonic IFN-I signaling in the brain following a COVID-19. This disruption would be mediated by the crosstalk between central and peripheral immunity, and could potentially establish feed-forward IFN-I dysregulation leading to neuroinflammation and potentially, neurodegeneration. We proposed that for the CNS, the second-order mediators would be intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without the requirement of neuroinvasion to sustain inflammation. Selective vulnerability of neurogenesis sites to IFN-I dysregulation would then lead to clinical manifestations such as anosmia and cognitive impairment. Since the inception of our model at the beginning of the pandemic, a growing body of studies has provided further evidence for the effects of SARS-CoV-2 infection on the human CNS and cognition. Several preclinical and clinical studies have displayed IFN-I dysregulation and tauopathy in gene expression and neuropathological data in new cases, correspondingly. Furthermore, neurodegeneration identified with a predilection for the extended olfactory network furthermore supports the neuroanatomical concept of our model, and its independence from fulminant neuroinvasion and encephalitis as a cause of CNS damage. In this perspective, we summarize the data on IFN-I as a plausible mechanism of cognitive impairment in this setting, and its potential contribution to Alzheimer’s disease and its interplay with COVID-19.

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“…Improper activation of STING, whether directly or indirectly, may lead to excessive inflammation and autoimmune diseases such as systemic lupus erythematosus and Acardi-Goutières Syndrome ( 8 – 11 ). Research has also found that the cGAS-STING pathway in innate immunity contributes to Alzheimer’s disease ( 12 , 13 ). In recent years, blocking the STING signal has emerged as a potential therapeutic target for various musculoskeletal diseases.…”

Section: Introductionmentioning

confidence: 99%

STING signaling in inflammaging: a new target against musculoskeletal diseases

Song

et al. 2023

Front. Immunol.

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Stimulator of Interferon Gene (STING) is a critical signaling linker protein that plays a crucial role in the intrinsic immune response, particularly in the cytoplasmic DNA-mediated immune response in both pathogens and hosts. It is also involved in various signaling processes in vivo. The musculoskeletal system provides humans with morphology, support, stability, and movement. However, its aging can result in various diseases and negatively impact people’s lives. While many studies have reported that cellular aging is a leading cause of musculoskeletal disorders, it also offers insight into potential treatments. Under pathological conditions, senescent osteoblasts, chondrocytes, myeloid cells, and muscle fibers exhibit persistent senescence-associated secretory phenotype (SASP), metabolic disturbances, and cell cycle arrest, which are closely linked to abnormal STING activation. The accumulation of cytoplasmic DNA due to chromatin escape from the nucleus following DNA damage or telomere shortening activates the cGAS-STING signaling pathway. Moreover, STING activation is also linked to mitochondrial dysfunction, epigenetic modifications, and impaired cytoplasmic DNA degradation. STING activation upregulates SASP and autophagy directly and indirectly promotes cell cycle arrest. Thus, STING may be involved in the onset and development of various age-related musculoskeletal disorders and represents a potential therapeutic target. In recent years, many STING modulators have been developed and used in the study of musculoskeletal disorders. Therefore, this paper summarizes the effects of STING signaling on the musculoskeletal system at the molecular level and current understanding of the mechanisms of endogenous active ligand production and accumulation. We also discuss the relationship between some age-related musculoskeletal disorders and STING, as well as the current status of STING modulator development.

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Aβ Induces Neuroinflammation and Microglial M1 Polarization via cGAS-STING-IFITM3 Signaling Pathway in BV-2 Cells

Cited by 13 publications

References 39 publications

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer’s disease

STING signaling in inflammaging: a new target against musculoskeletal diseases

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