scholarly journals TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Tong Li ◽  
Seoyun Yum ◽  
Minghao Li ◽  
Xiang Chen ◽  
Xiaoxia Zuo ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Strategy ◽  
Inflammatory Diseases ◽  
Type I Interferons ◽  
Type I ◽  
Disease Manifestation ◽  
Dnase Ii ◽  
Interferon Induction ◽  
Tnf Α

Defective DNA clearance in DNase II−/− mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II−/− mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II−/−STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II−/− mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.

scholarly journals Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 951 ◽  
Author(s):  
Mei Min Mah ◽  
Nicola Roverato ◽  
Marcus Groettrup
Keyword(s):  
Covalent Binding ◽  
Type I ◽  
Human Major Histocompatibility Complex ◽  
Binding Partners ◽  
Histocompatibility Complex ◽  
Interferon Induction ◽  
Tnf Α ◽  
Ifn Γ ◽  
Necrosis Factor

The revelation that the human major histocompatibility complex (MHC) class I locus encodes a ubiquitin-like protein designated HLA-F adjacent transcript 10 (FAT10) or ubiquitin D (UBD) has attracted increasing attention to the function of this protein. Interestingly, the pro-inflammatory cytokines interferon (IFN)-γ and tumor necrosis factor (TNF) α synergize to strongly induce FAT10 expression, thereby suggesting a role of FAT10 in the immune response. Recent reports that FAT10 downregulates type I interferon production while it upregulates IFN-γ pose mechanistic questions on how FAT10 differentially regulates interferon induction. Several covalent and non-covalent binding partners of FAT10 involved in signal transduction pathways leading to IFN synthesis have been identified. After introducing FAT10, we review here recent insights into how FAT10 affects proteins in the interferon pathways, like the virus-responsive pattern recognition receptor RIG-I, the ubiquitin ligase ZNF598, and the deubiquitylating enzyme OTUB1. Moreover, we outline the consequences of FAT10 deficiency on interferon synthesis and viral expansion in mice and human cells. We discuss the need for covalent isopeptide linkage of FAT10 to the involved target proteins and the concomitant targeting for proteasomal degradation. After years of investigating the elusive biological functions of this fascinating ubiquitin-like modifier, we review the emerging evidence for a novel role of FAT10 in interferon regulation.

scholarly journals Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Yuki Murakami ◽  
Masato Hoshi ◽  
Yukio Imamura ◽  
Yuko Arioka ◽  
Yasuko Yamamoto ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Type I Interferons ◽  
Regulatory Function ◽  
Type I ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Metabolites

Indoleamine 2,3-dioxygenase 1 (IDO1), the L-tryptophan-degrading enzyme, plays a key role in the immunomodulatory effects on several types of immune cells. Originally known for its regulatory function during pregnancy and chronic inflammation in tumorigenesis, the activity of IDO1 seems to modify the inflammatory state of infectious diseases. The pathophysiologic activity of L-tryptophan metabolites, kynurenines, is well recognized. Therefore, an understanding of the regulation of IDO1 and the subsequent biochemical reactions is essential for the design of therapeutic strategies in certain immune diseases. In this paper, current knowledge about the role of IDO1 and its metabolites during various infectious diseases is presented. Particularly, the regulation of type I interferons (IFNs) production via IDO1 in virus infection is discussed. This paper offers insights into new therapeutic strategies in the modulation of viral infection and several immune-related disorders.

scholarly journals RNA Helicase DDX3 Interacts with the Capsid Protein of Hepatitis E Virus and Plays an Indispensable Role in the Viral Replication

2020 ◽  
Author(s):  
Shaoli Lin ◽  
Peixi Chang ◽  
Jia He ◽  
Etienne Coyaud ◽  
Brian Pierce ◽  
...  
Keyword(s):  
Viral Replication ◽  
Capsid Protein ◽  
Hepatitis E Virus ◽  
Direct Interaction ◽  
Hepatitis E ◽  
Rna Helicase ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Induction

DDX3 is an ATP-dependent RNA helicase involved in multiple cellular activities, including RNA metabolism and innate immunity. DDX3 is known to assist the replication of some viruses while restricting some others through direct interaction with the viral proteins. However, the role of DDX3 in the replication of the hepatitis E virus (HEV) is unknown. In this study, DDX3 is shown to interact with the HEV capsid protein and provide an indispensable role in HEV replication. The DDX3 C-terminal domain was demonstrated to interact with the capsid protein, which was previously demonstrated to inhibit the production of type I interferons. Knockdown of DDX3 compromised the capsid protein-mediated blockage of interferon induction. Notably, DDX3 silencing led to a significant reduction in HEV replication. Also, the ATPase activity of DDX3 is required for the HEV replication as an ATPase-null mutant DDX3 failed to rescue the viral replication in the DDX3-silenced cells. These results demonstrate a pro-viral role of DDX3 in HEV replication, providing further insights into the virus-cell interactions.

The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria

2009 ◽  
Vol 5 (2) ◽  
pp. 143-149
Author(s):  
Marja Ojaniemi ◽  
Mari Liljeroos ◽  
Reetta Vuolteenaho
Keyword(s):  
Type I Interferons ◽  
Host Responses ◽  
Type I ◽  
Toll Like Receptors

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

scholarly journals A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons

2017 ◽  
Vol 282 (6) ◽  
pp. 522-536 ◽  
Author(s):  
K. H. Simons ◽  
H. A. B. Peters ◽  
J. W. Jukema ◽  
M. R. de Vries ◽  
P. H. A. Quax
Keyword(s):  
Vein Graft ◽  
Protective Role ◽  
Type I Interferons ◽  
Type I ◽  
Vein Graft Disease ◽  
Graft Disease

CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels

2004 ◽  
Vol 92 (08) ◽  
pp. 419-424 ◽  
Author(s):  
Stefan Blankenberg ◽  
Christine Espinola-Klein ◽  
Joern Dopheide ◽  
Christoph Bickel ◽  
Karl Lackner ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Animal Studies ◽  
Inflammatory Diseases ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Hs Crp ◽  
Artery Disease ◽  
Fourth Quartile

SummaryMonocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-α, and are elevated in various inflammatory diseases. We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-α, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16+ monocytes than controls (13.6% versus 11.4%; p<0.001). Logistic regression analysis including quartiles of CD14+CD16+ monocytes showed that CD14+CD16+ monocytes were associated with prevalence of CAD (OR 4.9, 95% CI 2.5–19.1, for subjects in the fourth quartile in comparison to subjects in the first quartile). The association between CD14+CD16+ monocytes and CAD remained independently significant after adjustment for most potential confounders (OR 5.0, 95% CI 1.2-20.0). Serum concentrations of TNF-α were elevated in subjects within the highest quartiles of CD14+CD16+ monocytes (p=0.018). Our study showed that increased numbers of CD14+CD16+ monocytes are associated with coronary atherosclerosis and TNF-α. In accordance, recent animal studies suggest a possibly important role of these monocytes in the development of atherosclerosis.

scholarly journals THE ROLE OF TYPE-I INTERFERONS IN POLY I:C INDUCED SICKNESS BEHAVIOUR

2014 ◽  
Vol 8 ◽  
Author(s):  
Murray Carol ◽  
O Loughlin Elaine ◽  
Cunningham Colm
Keyword(s):  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Sickness Behaviour
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