scholarly journals TYPE I INTERFERON-MEDIATED NEUROINFLAMMATORY PROGRAM AND SYNAPSE LOSS IN ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S92-S92
Author(s):  
Ethan Roy ◽  
Baiping Wang ◽  
Hui Zheng ◽  
Wei Cao
Keyword(s):  
Amyloid Fibrils ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Family Type ◽  
Complement C3 ◽  
Slice Culture ◽  
Type I ◽  
Hippocampal Slice Culture ◽  
Synapse Loss

Abstract The cytokine family type I interferon (IFN) is a major innate immune mediator extensively studied in the peripheral immune responses but largely under-investigated in AD. Previously, we established that innate immune cells readily produce IFN in response to amyloid fibrils containing nucleic acids as cofactor. Here, we investigated whether IFN pathway is associated with amyloidosis in AD brain and contributes to neuroinflammation. By systemically characterizing neuroinflammation in multiple murine AD models, we established a comprehensive core AD neuroinflammation profile that includes several key proinflammatory cytokine families, among which IFN pathway is consistently activated. When hippocampal slice culture was stimulated with different forms of amyloid fibrils, nucleic acid-containing amyloid fibrils, but not heparin-containing fibrils, potently activated IFN pathway and triggered comprehensive neuroinflammation. In addition, stereotaxic administration of IFNβ induced an immune response in the brain of wild type mice analogous to the core neuroinflammatory profile associated with Aβ pathology; whereas selective IFN receptor blockade significantly blunted the ongoing microgliosis in AD models in vivo. Furthermore, IFN promoted microglia-mediated synapse uptake from neurons, which depended on the induction of complement C3, and blockade of IFN signaling significantly abolished the pathogenic synapse loss in AD brain. Consistent with the findings in mice, we found that genes stimulated by IFN were grossly upregulated in human AD brains. Therefore, type I interferon constitutes a major pathway within the neuroinflammatory network of AD and may represent a molecular target to restrain the pathogenic inflammatory responses.

scholarly journals Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

2020 ◽  
Author(s):  
Yuanjiu Lei ◽  
Camila Guerra Martinez ◽  
Sylvia Torres-Odio ◽  
Samantha L. Bell ◽  
Christine E. Birdwell ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Aerobic Glycolysis ◽  
Accelerated Aging ◽  
Innate Immune ◽  
Related Factor ◽  
Type I ◽  
Metabolic Dysfunction ◽  
Polymerase Gamma

AbstractMitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

scholarly journals Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

2021 ◽  
Vol 7 (22) ◽  
pp. eabe7548
Author(s):  
Yuanjiu Lei ◽  
Camila Guerra Martinez ◽  
Sylvia Torres-Odio ◽  
Samantha L. Bell ◽  
Christine E. Birdwell ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Aerobic Glycolysis ◽  
Accelerated Aging ◽  
Innate Immune ◽  
Related Factor ◽  
Type I ◽  
Metabolic Dysfunction ◽  
Elevated Type

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2–related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging.

scholarly journals Regulatory NLRs Control the RLR-Mediated Type I Interferon and Inflammatory Responses in Human Dendritic Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Tünde Fekete ◽  
Dora Bencze ◽  
Attila Szabo ◽  
Eszter Csoma ◽  
Tamas Biro ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Type I ◽  
Human Dendritic Cells

Type I Interferon Regulates Antiviral And Inflammatory Responses To Rhinovirus Infection In Vivo

2011 ◽  
Author(s):  
Nathan W. Bartlett ◽  
Ross P. Walton ◽  
Michael R. Edwards ◽  
Bethan Warwick ◽  
Sebastian L. Johnston
Keyword(s):  
Inflammatory Responses ◽  
Type I Interferon ◽  
Type I ◽  
Rhinovirus Infection

scholarly journals Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

2015 ◽  
Vol 90 (5) ◽  
pp. 2403-2417 ◽  
Author(s):  
Chuan Xia ◽  
Madhuvanthi Vijayan ◽  
Curtis J. Pritzl ◽  
Serge Y. Fuchs ◽  
Adrian B. McDermott ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

scholarly journals Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Xiaoqiong Duan ◽  
Yujuan Guan ◽  
Yujia Li ◽  
Shan Chen ◽  
Shilin Li ◽  
...  
Keyword(s):  
Vitamin D ◽  
Type I Interferon ◽  
Inhibitory Effect ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Type I ◽  
Interferon Signaling ◽  
Host Innate Immune Response ◽  
Antiviral Mechanism

Calcitriol, the bioactive metabolite of vitamin D, was reported to inhibit HCV production in a synergistic fashion with interferon, a treatmentin vitro. Our previous study established that miR-130a inhibits HCV replication by restoring the host innate immune response. We aimed to determine whether there is additive inhibitory effect of calcitriol and miR-130a on HCV replication. Here we showed that calcitriol potentiates the anti-HCV effect of miR-130a in both Con1b replicon and J6/JFH1 culture systems. Intriguingly, this potentiating effect of calcitriol on miR-130a was not through upregulating the expression of cellular miR-130a or through increasing the miR-130a-mediated IFNα/βproduction. All these findings may contribute to the development of novel anti-HCV therapeutic strategies although the antiviral mechanism needs to be further investigated.

scholarly journals Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zhou Yu ◽  
Taoyong Chen ◽  
Xuelian Li ◽  
Mingjin Yang ◽  
Songqing Tang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I ◽  
Innate Response ◽  
Scf Complex ◽  
Protein Ubiquitination ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Unknown Component

Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1–Cul1–F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.

scholarly journals The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Yong Hu ◽  
Wei Li ◽  
Ting Gao ◽  
Yan Cui ◽  
Yanwen Jin ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Innate Immune ◽  
Atypical Pneumonia ◽  
Type I ◽  
Spry Domain ◽  
N Protein ◽  
Host Interaction ◽  
C Terminus

ABSTRACT Severe acute respiratory syndrome (SARS) is a respiratory disease, caused by a coronavirus (SARS-CoV), that is characterized by atypical pneumonia. The nucleocapsid protein (N protein) of SARS-CoV plays an important role in inhibition of type I interferon (IFN) production via an unknown mechanism. In this study, the SARS-CoV N protein was found to bind to the SPRY domain of the tripartite motif protein 25 (TRIM25) E3 ubiquitin ligase, thereby interfering with the association between TRIM25 and retinoic acid-inducible gene I (RIG-I) and inhibiting TRIM25-mediated RIG-I ubiquitination and activation. Type I IFN production induced by poly I·C or Sendai virus (SeV) was suppressed by the SARS-CoV N protein. SARS-CoV replication was increased by overexpression of the full-length N protein but not N amino acids 1 to 361, which could not interact with TRIM25. These findings provide an insightful interpretation of the SARS-CoV-mediated host innate immune suppression caused by the N protein. IMPORTANCE The SARS-CoV N protein is essential for the viral life cycle and plays a key role in the virus-host interaction. We demonstrated that the interaction between the C terminus of the N protein and the SPRY domain of TRIM25 inhibited TRIM25-mediated RIG-I ubiquitination, which resulted in the inhibition of IFN production. We also found that the Middle East respiratory syndrome CoV (MERS-CoV) N protein interacted with TRIM25 and inhibited RIG-I signaling. The outcomes of these findings indicate the function of the coronavirus N protein in modulating the host's initial innate immune response.

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