Cutting Edge: Critical Role of IκB Kinase α in TLR7/9-Induced Type I IFN Production by Conventional Dendritic Cells

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in RIG-I translocation to MAVS to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-β promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-β expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49 th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C-terminus-truncated NS1 with T49A mutation dramatically increases IFN-β mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-β expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in RIG-I translocation that induces type I IFN expression, and that NS1 protein prevents RIG-I translocation to mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-β suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.

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cGAS/STING/TBK1/IRF3 Signaling Pathway Activates BMDCs Maturation Following Mycobacterium bovis Infection

International Journal of Molecular Sciences ◽

10.3390/ijms20040895 ◽

2019 ◽

Vol 20 (4) ◽

pp. 895 ◽

Cited By ~ 6

Author(s):

Qiang Li ◽

Chunfa Liu ◽

Ruichao Yue ◽

Saeed El-Ashram ◽

Jie Wang ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Mycobacterium Bovis ◽

New Drugs ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Innate Immune Responses ◽

Dependent Signal

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4+ T cells’ proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.

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IFN-β signalling regulates RAW 264.7 macrophage activation, cytokine production, and killing activity

Innate Immunity ◽

10.1177/1753425919878839 ◽

2019 ◽

Vol 26 (3) ◽

pp. 172-182

Author(s):

Yalda Karimi ◽

Elizabeth C Giles ◽

Fatemeh Vahedi ◽

Marianne V Chew ◽

Tina Nham ◽

...

Keyword(s):

Inflammatory Response ◽

Bacterial Infections ◽

Viral Infections ◽

Critical Role ◽

Raw 264.7 ◽

Type I ◽

Type I Ifn ◽

Killing Activity ◽

Raw 264.7 Macrophage

Type I IFN holds a critical role in host defence, providing protection against pathogenic organisms through coordinating a pro-inflammatory response. Type I IFN provides additional protection through mitigating this inflammatory response, preventing immunopathology. Within the context of viral infections, type I IFN signalling commonly results in successful viral clearance. Conversely, during bacterial infections, the role of type I IFN is less predictable, leading to either detrimental or beneficial outcomes. The factors responsible for the variability in the role of type I IFN remain unclear. Here, we aimed to elucidate differences in the effect of type I IFN signalling on macrophage functioning in the context of TLR activation. Using RAW 264.7 macrophages, we observed the influence of type I IFN to be dependent on the type of TLR ligand, length of TLR exposure and the timing of IFN-β signalling. However, in all conditions, IFN-β increased the production of the anti-inflammatory cytokine IL-10. Examination of RAW 264.7 macrophage function showed type I IFN to induce an activated phenotype by up-regulating MHC II expression and enhancing killing activity. Our results support a context-dependent role for type I IFN in regulating RAW 264.7 macrophage activity.

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Cutting Edge: IFN Consensus Sequence Binding Protein/IFN Regulatory Factor 8 Drives the Development of Type I IFN-Producing Plasmacytoid Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.170.3.1131 ◽

2003 ◽

Vol 170 (3) ◽

pp. 1131-1135 ◽

Cited By ~ 172

Author(s):

Hideki Tsujimura ◽

Tomohiko Tamura ◽

Keiko Ozato

Keyword(s):

Dendritic Cells ◽

Binding Protein ◽

Consensus Sequence ◽

Plasmacytoid Dendritic Cells ◽

Cutting Edge ◽

Type I ◽

Type I Ifn ◽

Regulatory Factor

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Cutting Edge: TLR-Dependent Viral Recognition Along with Type I IFN Positive Feedback Signaling Masks the Requirement of Viral Replication for IFN-α Production in Plasmacytoid Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.0804315 ◽

2009 ◽

Vol 182 (7) ◽

pp. 3960-3964 ◽

Cited By ~ 68

Author(s):

Yutaro Kumagai ◽

Himanshu Kumar ◽

Shohei Koyama ◽

Taro Kawai ◽

Osamu Takeuchi ◽

...

Keyword(s):

Dendritic Cells ◽

Viral Replication ◽

Positive Feedback ◽

Plasmacytoid Dendritic Cells ◽

Cutting Edge ◽

Type I ◽

Type I Ifn ◽

Viral Recognition

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Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

Nature Communications ◽

10.1038/s41467-021-23003-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Junji Xing ◽

Ao Zhang ◽

Yong Du ◽

Mingli Fang ◽

Laurie J. Minze ◽

...

Keyword(s):

Dendritic Cells ◽

Protective Immunity ◽

Viral Infections ◽

Rna Virus ◽

Critical Role ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Mitochondrial Antiviral Signaling ◽

Phosphoinositide 3 Kinase

AbstractInnate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.

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A type I IFN–Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors

Journal of Experimental Medicine ◽

10.1084/jem.20130536 ◽

2013 ◽

Vol 210 (12) ◽

pp. 2515-2522 ◽

Cited By ~ 33

Author(s):

Yi-Ling Chen ◽

Ting-Ting Chen ◽

Li-Mei Pai ◽

Joanna Wesoly ◽

Hans A.R. Bluyssen ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cell ◽

Critical Role ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Flt3 Ligand ◽

Lymphoid Progenitors

During infections and inflammation, plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I)–producing cells. However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, whereas pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor, impairment of IFN-I signaling, or neutralization of IFN-I significantly impeded pDC development from CLPs. Furthermore, FL induced IFN-I expression in CLPs, which in turn induced Flt3 up-regulation that facilitated survival and proliferation of CLPs, as well as their differentiation into pDCs. Collectively, these results define a critical role for the FL/IFN-I/Flt3 axis in pDC differentiation from CLPs.

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Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0505251102 ◽

2005 ◽

Vol 102 (39) ◽

pp. 13974-13979 ◽

Cited By ~ 122

Author(s):

J.-P. Herbeuval ◽

A. W. Hardy ◽

A. Boasso ◽

S. A. Anderson ◽

M. J. Dolan ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Hiv 1

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CpG-matured Murine Plasmacytoid Dendritic Cells Are Capable of In Vivo Priming of Functional CD8 T Cell Responses to Endogenous but Not Exogenous Antigens

Journal of Experimental Medicine ◽

10.1084/jem.20031059 ◽

2004 ◽

Vol 199 (4) ◽

pp. 567-579 ◽

Cited By ~ 131

Author(s):

Mariolina Salio ◽

Michael J. Palmowski ◽

Ann Atzberger ◽

Ian F. Hermans ◽

Vincenzo Cerundolo

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Antiviral Responses ◽

Specific Ctls ◽

Antigen Presenting

Plasmacytoid dendritic cells (PDCs) are a unique leukocyte population capable of secreting high levels of type I interferon (IFN) in response to viruses and bacterial stimuli. In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed. We report that CpG-matured murine PDCs are capable of eliciting in naive mice antigen-specific CTLs against endogenous antigens as well as exogenous peptides, but not against an exogenous antigen. Type I IFN is not required for priming, as injection of CpG-matured PDCs into type I IFN receptor–deficient mice elicits functional CTL responses. Mature PDCs prime CTLs that secrete IFN-γ and protect mice from a tumor challenge. In contrast, immature PDCs are unable to prime antigen-specific CTLs. However, mice injected with immature PDCs are fully responsive to secondary antigenic challenges, suggesting that PDCs have not induced long-lasting tolerance via anergic or regulatory T cells. Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

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