A type I interferon autocrine–paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells

Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-κB (NF-κB)–dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-β mRNA accumulation by mouse bone marrow–derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1−/− and IFNAR−/− mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-β mRNA accumulation were strongly inhibited in IFNAR−/− BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-λ1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-κB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.

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Faculty Opinions recommendation of A type I IFN-dependent pathway induced by Schistosoma mansoni eggs in mouse myeloid dendritic cells generates an inflammatory signature.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1017690.203302 ◽

2004 ◽

Author(s):

George Yap

Keyword(s):

Dendritic Cells ◽

Schistosoma Mansoni ◽

Type I ◽

Type I Ifn ◽

Myeloid Dendritic Cells ◽

Dependent Pathway

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Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites

Viruses ◽

10.3390/v12010043 ◽

2019 ◽

Vol 12 (1) ◽

pp. 43 ◽

Cited By ~ 6

Author(s):

Si Chen ◽

Jin Tian ◽

Zhijie Li ◽

Hongtao Kang ◽

Jikai Zhang ◽

...

Keyword(s):

Type I Interferon ◽

Sendai Virus ◽

Nuclear Factor Κb ◽

Poly I:C ◽

Type I ◽

Dependent Manner ◽

Type I Ifn ◽

Feline Infectious Peritonitis Virus ◽

Feline Infectious Peritonitis ◽

Polycytidylic Acid

Feline infectious peritonitis (FIP), caused by virulent feline coronavirus, is the leading infectious cause of death in cats. The type I interferon (type I IFN)-mediated immune responses provide host protection from infectious diseases. Several coronaviruses have been reported to evolve diverse strategies to evade host IFN response. However, whether feline infectious peritonitis virus (FIPV) antagonizes the type I IFN signaling remains unclear. In this study, we demonstrated that FIPV strain DF2 infection not only failed to induce interferon-β (IFN-β) and interferon-stimulated gene (ISG) production, but also inhibited Sendai virus (SEV) or polyinosinic-polycytidylic acid (poly(I:C))-induced IFN-β production. Subsequently, we found that one of the non-structural proteins encoded by the FIPV genome, nsp5, interrupted type I IFN signaling in a protease-dependent manner by cleaving the nuclear factor κB (NF-κB) essential modulator (NEMO) at three sites—glutamine132 (Q132), Q205, and Q231. Further investigation revealed that the cleavage products of NEMO lost the ability to activate the IFN-β promoter. Mechanistically, the nsp5-mediated NEMO cleavage disrupted the recruitment of the TRAF family member-associated NF-κB activator (TANK) to NEMO, which reduced the phosphorylation of interferon regulatory factor 3 (IRF3), leading to the inhibition of type I IFN production. Our research provides new insights into the mechanism for FIPV to counteract host innate immune response.

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Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37

Blood ◽

10.1182/blood-2012-01-401364 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3699-3707 ◽

Cited By ~ 92

Author(s):

Georgios Chamilos ◽

Josh Gregorio ◽

Stephan Meller ◽

Roberto Lande ◽

Dimitrios P. Kontoyiannis ◽

...

Keyword(s):

Dendritic Cells ◽

Antimicrobial Peptide ◽

Methylation Status ◽

Adaptor Protein ◽

Extracellular Dna ◽

Type I ◽

Type I Ifn ◽

Toll Like Receptor ◽

Intracellular Location ◽

Type I Ifns

Abstract The intracellular location of nucleic acid sensors prevents recognition of extracellular self-DNA released by dying cells. However, on forming a complex with the endogenous antimicrobial peptide LL37, extracellular DNA is transported into endosomal compartments of plasmacytoid dendritic cells, leading to activation of Toll-like receptor-9 and induction of type I IFNs. Whether LL37 also transports self-DNA into nonplasmacytoid dendritic cells, leading to type I IFN production via other intracellular DNA receptors is unknown. Here we found that LL37 very efficiently transports self-DNA into monocytes, leading the production of type I IFNs in a Toll-like receptor-independent manner. This type I IFN induction was mediated by double-stranded B form DNA, regardless of its sequence, CpG content, or methylation status, and required signaling through the adaptor protein STING and TBK1 kinase, indicating the involvement of cytosolic DNA sensors. Thus, our study identifies a novel link between the antimicrobial peptides and type I IFN responses involving DNA-dependent activation of cytosolic sensors in monocytes.

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Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

Journal of Virology ◽

10.1128/jvi.01051-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 9760-9774 ◽

Cited By ~ 97

Author(s):

Juan R. Rodriguez-Madoz ◽

Alan Belicha-Villanueva ◽

Dabeiba Bernal-Rubio ◽

Joseph Ashour ◽

Juan Ayllon ◽

...

Keyword(s):

Dendritic Cells ◽

Dengue Virus ◽

Type I Interferon ◽

Poly I:C ◽

Interferon Response ◽

Type I ◽

Type I Ifn ◽

Human Virus ◽

Catalytically Active ◽

Human Dendritic Cells

ABSTRACT Dengue virus (DENV) is the most prevalent arthropod-borne human virus, able to infect and replicate in human dendritic cells (DCs), inducing their activation and the production of proinflammatory cytokines. However, DENV can successfully evade the immune response in order to produce disease in humans. Several mechanisms of immune evasion have been suggested for DENV, most of them involving interference with type I interferon (IFN) signaling. We recently reported that DENV infection of human DCs does not induce type I IFN production by those infected DCs, impairing their ability to prime naive T cells toward Th1 immunity. In this article, we report that DENV also reduces the ability of DCs to produce type I IFN in response to several inducers, such as infection with other viruses or exposure to Toll-like receptor (TLR) ligands, indicating that DENV antagonizes the type I IFN production pathway in human DCs. DENV-infected human DCs showed a reduced type I IFN response to Newcastle disease virus (NDV), Sendai virus (SeV), and Semliki Forest virus (SFV) infection and to the TLR3 agonist poly(I:C). This inhibitory effect is DENV dose dependent, requires DENV replication, and takes place in DENV-infected DCs as early as 2 h after infection. Expressing individual proteins of DENV in the presence of an IFN-α/β production inducer reveals that a catalytically active viral protease complex is required to reduce type I IFN production significantly. These results provide a new mechanism by which DENV evades the immune system in humans.

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Thogoto Virus Infection Induces Sustained Type I Interferon Responses That Depend on RIG-I-Like Helicase Signaling of Conventional Dendritic Cells

Journal of Virology ◽

10.1128/jvi.00931-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12344-12350 ◽

Cited By ~ 11

Author(s):

Georg Kochs ◽

Stefanie Bauer ◽

Carola Vogt ◽

Theresa Frenz ◽

Jürg Tschopp ◽

...

Keyword(s):

Dendritic Cells ◽

Host Defense ◽

Viral Infections ◽

Type I Interferon ◽

Type I ◽

Type I Ifn ◽

Toll Like Receptor ◽

Tlr Signaling ◽

The Matrix ◽

Interferon Responses

ABSTRACT Type I interferon (IFN-α/β) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is conferred by specialized plasmacytoid dendritic cells (pDC) and may depend on positive-feedback amplification via the type I IFN receptor (IFNAR). Here, we show that mice infected with Thogoto virus (THOV), which is an influenza virus-like orthomyxovirus transmitted by ticks, mounted sustained IFN responses that persisted up to 72 h after infection. For this purpose, we used a variant of THOV lacking its IFN-antagonistic protein ML, an elongated version of the matrix (M) protein [THOV(ΔML)]. Of note, large amounts of type I IFN were also found in the serum of mice lacking the IFNAR. Early IFN-α expression seemed to depend on Toll-like receptor (TLR) signaling, whereas prolonged IFN-α responses strictly depended on RIG-I-like helicase (RLH) signaling. Unexpectedly, THOV(ΔML)-infected bone marrow-derived pDC (BM-pDC) produced only moderate IFN levels, whereas myeloid DC (BM-mDC) showed massive IFN induction that was IPS-1-dependent, suggesting that BM-mDC are involved in the massive, sustained IFN production in THOV(ΔML)-infected animals. Thus, our data are compatible with the model that THOV(ΔML) infection is sensed in the acute phase via TLR and RLH systems, whereas at later time points only RLH signaling is responsible for the induction of sustained IFN responses.

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Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Journal of Virology ◽

10.1128/jvi.00023-08 ◽

2008 ◽

Vol 83 (2) ◽

pp. 884-895 ◽

Cited By ~ 56

Author(s):

Susanna Trapp ◽

Nina R. Derby ◽

Rachel Singer ◽

Andrew Shaw ◽

Vennansha G. Williams ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Dendritic Cells ◽

Hiv Infection ◽

Molecular Mass ◽

Type I Interferon ◽

Poly I:C ◽

Interleukin 12 ◽

Type I ◽

Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs), which can then transfer virus to T cells, amplifying the infection. Strategies known to boost DC function were tested for their ability to overcome this exploitation when added after HIV exposure. Poly(I:C), but not single-stranded RNA (ssRNA) or a standard DC maturation cocktail, elicited type I interferon (IFN) and interleukin-12 (IL-12) p70 production and the appearance of unique small (15- to 20-kDa) fragments of APOBEC3G (A3G) and impeded HIVBal replication in imDCs when added up to 60 h after virus exposure. Comparable effects were mediated by recombinant alpha/beta IFN (IFN-α/β). Neutralizing the anti-IFN-α/β receptor reversed poly(I:C)-induced inhibition of HIV replication and blocked the appearance of the small A3G proteins. The poly(I:C)-induced appearance of small A3G proteins was not accompanied by significant differences in A3G mRNA or A3G monomer expression. Small interfering RNA (siRNA) knockdown of A3G could not be used to reverse the poly(I:C)-induced protective effect, since siRNAs nonspecifically activated the DCs, inducing the appearance of the small A3G proteins and inhibiting HIV infection. Notably, the appearance of small A3G proteins coincided with the shift of high-molecular-mass inactive A3G complexes to the low-molecular-mass (LMM) active A3G complexes. The unique immune stimulation by poly(I:C) with its antiviral effects on imDCs marked by the expression of IFN-α/β and active LMM A3G renders poly(I:C) a promising novel strategy to combat early HIV infection in vivo.

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Vesicular Stomatitis Virus M Protein Mutant Stimulates Maturation of Toll-Like Receptor 7 (TLR7)-Positive Dendritic Cells through TLR-Dependent and -Independent Mechanisms

Journal of Virology ◽

10.1128/jvi.02030-08 ◽

2009 ◽

Vol 83 (7) ◽

pp. 2962-2975 ◽

Cited By ~ 33

Author(s):

Maryam Ahmed ◽

Latoya M. Mitchell ◽

Shelby Puckett ◽

Kristina L. Brzoza-Lewis ◽

Douglas S. Lyles ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Vesicular Stomatitis Virus ◽

Knockout Mice ◽

M Protein ◽

Type I ◽

Type I Ifn ◽

Toll Like Receptor ◽

Vesicular Stomatitis ◽

Dc Maturation

ABSTRACT Wild-type (wt) vesicular stomatitis virus (VSV) strains stimulate plasmacytoid dendritic cells (pDC) through Toll-like receptor 7 (TLR7) and its adaptor molecule, MyD88. Granulocyte-macrophage colony-stimulating factor-derived DC (G-DC), which do not express TLR7, are unresponsive to wt VSV due to inhibition of cellular gene expression by the matrix (M) protein. In contrast to its recombinant wt (rwt) counterpart, an M protein mutant of VSV, rM51R-M virus, stimulates maturation of G-DC independently of MyD88. These results suggest that, as in the case of G-DC, rM51R-M virus may stimulate pDC by mechanisms distinct from that by rwt virus. Studies presented here demonstrate that both rwt and rM51R-M viruses induced maturation of TLR7-positive DC derived by culture in the presence of Flt3L (F-DC), with the subsequent expression of type I interferon (IFN). F-DC are a mixture of myeloid (CD11b+) and plasmacytoid (B220+) DC, both of which respond to TLR7 ligands. Separated CD11b+ and B220+ F-DC responded to both rwt and rM51R-M viruses. Both viruses were also defective at inhibiting host gene expression in F-DC, including the expression of genes involved in the antiviral response. The data from F-DC generated from IFN receptor knockout mice demonstrated that the maturation of F-DC induced by rwt virus was dependent on the type I IFN response, while maturation induced by rM51R-M virus was partially dependent on this molecule. Therefore, activation of the type I IFN pathway appears to be important for not only inducing an antiviral response but also for stimulating maturation of F-DC upon virus infection. Importantly, F-DC from TLR7 and MyD88 knockout mice did not undergo maturation in response to rwt virus, while maturation induced by rM51R-M virus was largely independent of both molecules. These results indicate that although both viruses induce F-DC maturation, F-DC detect and respond to rM51R-M virus by means that are distinct from rwt virus. Specifically, this mutant virus appears capable of inducing DC maturation in a wide variety of DC subsets through TLR-dependent and independent mechanisms.

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