1000 Improvement in CDASI in cutaneous dermatomyositis correlates with change in type I interferons, CD4+ cells, and myeloid dendritic cells

ABSTRACT Alphaviruses are mosquito-transmitted viruses that cause significant human disease, and understanding how these pathogens successfully transition from the mosquito vector to the vertebrate host is an important area of research. Previous studies demonstrated that mosquito and mammalian-cell-derived alphaviruses differentially induce type I interferons (alpha/beta interferon [IFN-α/β]) in myeloid dendritic cells (mDCs), where the mosquito cell-derived virus is a poor inducer of IFN-α/β compared to the mammalian-cell-derived virus. Furthermore, the reduced IFN-α/β induction by the mosquito cell-derived virus is attributed to differential N-linked glycosylation (29). To further evaluate the role of viral envelope glycans in regulating the IFN-α/β response, studies were performed to assess whether the mosquito cell-derived virus actively inhibits IFN-α/β induction or is simply a poor inducer of IFN-α/β. Coinfection studies using mammalian- and mosquito cell-derived Ross River virus (mam-RRV and mos-RRV, respectively) indicated that mos-RRV was unable to suppress IFN-α/β induction by mam-RRV in mDC cultures. Additionally, a panel of mutant viruses lacking either individual or multiple N-linked glycosylation sites was used to demonstrate that N-linked glycans were essential for high-level IFN-α/β induction by the mammalian-cell-derived virus. These results suggest that the failure of the mosquito cell-derived virus to induce IFN-α/β is due to a lack of complex carbohydrates on the virion rather than the active suppression of the DC antiviral response.

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EBI2 Is a Negative Regulator of Type I Interferons in Plasmacytoid and Myeloid Dendritic Cells

PLoS ONE ◽

10.1371/journal.pone.0083457 ◽

2013 ◽

Vol 8 (12) ◽

pp. e83457 ◽

Cited By ~ 19

Author(s):

Eugene Y. Chiang ◽

Robert J. Johnston ◽

Jane L. Grogan

Keyword(s):

Dendritic Cells ◽

Negative Regulator ◽

Type I Interferons ◽

Type I ◽

Myeloid Dendritic Cells

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PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4808 ◽

2008 ◽

Vol 31 (4) ◽

pp. 13

Author(s):

Martin Hyrcza ◽

Mario Ostrowski ◽

Sandy Der

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Hiv Infection ◽

Gene Transcription ◽

Sendai Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

Journal of Virology ◽

10.1128/jvi.00818-14 ◽

2014 ◽

Vol 88 (16) ◽

pp. 9350-9360 ◽

Cited By ~ 52

Author(s):

S. A. Cormier ◽

B. Shrestha ◽

J. Saravia ◽

G. I. Lee ◽

L. Shen ◽

...

Keyword(s):

Dendritic Cells ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Respiratory Syncytial Virus Infection ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Type I ◽

Syncytial Virus

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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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IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

PLoS Pathogens ◽

10.1371/journal.ppat.1003118 ◽

2013 ◽

Vol 9 (1) ◽

pp. e1003118 ◽

Cited By ~ 177

Author(s):

Helen M. Lazear ◽

Alissa Lancaster ◽

Courtney Wilkins ◽

Mehul S. Suthar ◽

Albert Huang ◽

...

Keyword(s):

Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Myeloid Dendritic Cells

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The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling

Blood ◽

10.1182/blood-2011-08-371831 ◽

2012 ◽

Vol 119 (2) ◽

pp. 454-464 ◽

Cited By ~ 149

Author(s):

Cyril Seillet ◽

Sophie Laffont ◽

Florence Trémollières ◽

Nelly Rouquié ◽

Claude Ribot ◽

...

Keyword(s):

Dendritic Cells ◽

Estrogen Receptor ◽

Estrogen Receptor Α ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Type I ◽

Genetic Ablation ◽

17Β Estradiol ◽

Female Host

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7–mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7–mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7– and TLR-9–dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17β-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.

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