Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR 7 agonists

Birmachu, Woubalem; Gleason, Raymond M.; Bulbulian, Barbara J; Riter, Christie L; Vasilakos, John P.; Lipson, Kenneth E.; Nikolsky, Yuri

doi:10.1186/1471-2172-8-26

Cited by 67 publications

(61 citation statements)

References 115 publications

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“…10 Agonistic engagement of TLR7 also leads to the expression of the IFN-inducible genes mxa, cxcl10, and trail. 11 A type I IFN autocrine loop is thought to explain the expression of these genes, as has been described in mouse bone marrow-derived DCs. 12 However, the precise pathway downstream of TLR7 leading to human pDC activation remains to be determined.…”

Section: Introductionmentioning

confidence: 94%

TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

Domizio

Blum

Gallagher-Gambarelli

et al. 2009

Blood

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On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only lowlevel production of IFN-␣. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFNinducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response. IntroductionToll-like receptors (TLRs) contain a leucine-rich repeat ectodomain that enables the recognition of pathogen-associated molecular patterns. 1 Among the 10 TLRs identified in humans, TLR7 is the least studied. This TLR binds single-stranded viral RNA, localizes to endosomal compartments, and is particularly expressed by plasmacytoid dendritic cells (pDCs). 2 Ligand binding to TLR7 activates human pDCs that respond by either producing proinflammatory cytokines or substantial levels of type I IFN and activating specific T cells. [3][4][5] In addition, we have recently shown that Fluand TLR7 agonist-activated pDCs express TNF-related apoptosisinducing ligand (TRAIL). This renders them capable of direct cytotoxic activity toward infected and tumor cells. 6 This has been observed in vivo: Stary et al 7 describe the presence of TRAILexpressing and IFN-␣-producing pDCs in tumors after topical use of the TLR7 ligand imiquimod in basal cell carcinoma treatment. Taken together, these data suggest that pDCs represent key target cells in the striking antitumor effects observed with synthetic TLR7 agonists, such as imidazoquinolines, in the treatment of cutaneous virus-induced neoplasia (eg, condyloma-HPV), 8 and other skin tumors, such as basal cell carcinoma. 9 The signaling pathways triggered by TLR7 activation have been partially described. After ligand recognition, endosomal TLR7 interacts with the key adaptor molecule MyD88 (myeloid differentiation primary-response gene 88) that recruits a signal complex comprising IRAK1 (interleukin-1 receptor-associated kinase 1), IRAK4, and TRAF6 (tumor necrosis factor receptor-associated factor 6). TLR7 triggering leads to the activation of NF-B (nuclear factor-B) and MAPKs (mito...

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Section: Introductionmentioning

confidence: 94%

TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

Domizio

Blum

Gallagher-Gambarelli

et al. 2009

Blood

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“…Considering that all the IFN-␣ subtype mRNAs reached peak levels 4 hours after TLR7 stimulation, 29 we focused on the miRNAs that were induced in the early stage. Primary human PDCs purified from the PBMCs of 10 healthy donors were stimulated for 4 hours with R837, and the expression levels of mature miRNAs were measured.…”

Section: Identification Of Mirna Induction During Primary Human Pdc Amentioning

confidence: 99%

“…This is consistent with an earlier report. 29 Microarray analysis of the miRNAs showed that 174 of the 657 miRNAs screened were expressed in the PDCs (supplemental Table 3). Among these 174 miRNAs, 5 miRNAs were significantly increased (more than 4-fold), whereas 14 were significantly reduced (more than 4-fold; supplemental Table 3).…”

Section: Identification Of Mirna Induction During Primary Human Pdc Amentioning

confidence: 99%

miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells

Zhou

Huang

Cui

et al. 2010

Blood

236

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The recent discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation, affecting the immune system. Here, we identify their roles in regulating human plasmacytoid dendritic cell (PDC) activation. miRNA profiling showed the significantly differential expression of 19 miRNAs in PDCs after Toll-like receptor 7 (TLR7) stimulation, among which miR-155* and miR-155 were the most highly induced. Although they were processed from a single precursor and were both induced by TLR7 through the c-Jun N-terminal kinase pathway, miR-155* and miR-155 had opposite effects on the regulation of type I interferon production by PDC. IntroductionPlasmacytoid dendritic cell (PDC) is a distinct dendritic cell type, specialized for the rapid secretion of type I interferon (type I IFN) in response to viruses. [1][2][3] It has been demonstrated that PDCs can coordinate events during the course of viral infection, autoimmune diseases, and cancer. PDCs, through their production of interferon-␣ (IFN-␣) and other cytokines, and through antigen presentation, link the innate and adaptive immune responses. 3 PDC deficiency, leading to low levels of IFN-␣ production, results in an inadequate immune response, entailing susceptibility to viral infections or cancer, whereas excessive secretion of IFN-␣ can induce hyperimmune activation, which may lead to autoimmune disease or, in the case of HIV infection, CD4 ϩ T-cell death. [2][3][4][5] Therefore, type I IFN production by PDCs must be under tight control to prevent improper immune responses, which could be harmful to the host. 2,3 PDCs express high levels of Toll-like receptor 7 (TLR7) and TLR9. The interaction between TLR7/9 and their ligands leads to the activation of the myeloid differentiation primary response gene 88/IL-1/4 receptor-associated kinase/tumor necrosis factor (TNF) receptor-associated factor 6/IB kinases (MyD88/IRAK1/4/TRAF6/ IKKs) pathway and the subsequent phosphorylation of interferonregulatory receptor 7 (IRF-7), which is translocated into the nucleus and initiates IFN-␣ transcription. 2,6 The phosphatidylinositol 3-kinase/Av-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway and p38 mitogen-activated protein kinase (MAPK) activity have also been shown to positively regulate type I IFN production. 7,8 In contrast to these positive regulators, an array of surface receptors on PDCs, such as blood dendritic cell antigen 2 (BDCA2), dendritic cell immunoreceptor (DCIR), immunoglobulin-like transcript 7 (ILT7), high-affinity immunoglobulin E receptor (Fc⑀RI), and natural killer partner 44 (NKp44), are reported to signal through a powerful immunoreceptor tyrosine-based activation motif (ITAM)-mediated, B-cell receptor (BCR)-like regulatory pathway to counter-regulate the prominent TLR signaling pathway. 2,9-13 Although the kinetics of type I IFN production by human PDCs have been investigated in detail, 14 the dynamic regulatory mechanism has not yet been clarified. Both TLR7 and TLR9 are considered closely ...

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“…The PDCs selectively express CD123, BDCA-2, BDCA-4 Ags, TLR7, and TLR9 and are principal producers of IFN-␣ (12)(13)(14)(15)(16)(17). Upon stimulation with TLR9 ligands, like unmethylated CpG DNA, herpes simplex virus type 1 and herpes simplex virus type 2 genomic DNA, and TLR7 ligands, like single-stranded RNA viruses, PDCs produce large amounts of IFN-␣, besides production of proinflammatory cytokines TNF-␣, IL-6, and IL-8 (12,(17)(18)(19)(20). The ability of PDCs to produce high amounts of IFN-␣ compared with other cell types is mainly attributed to constitutive expression of IFN regulatory factor (IRF)-7, which is required for the stimulation of IFN-␣ gene expression (21,22).…”

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confidence: 99%

Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-α but Not Proinflammatory Cytokines

Sachdeva

Asthana

Brewer

et al. 2008

The Journal of Immunology

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We analyzed reconstitution characteristics of plasmacytoid dendritic cells (PDCs) and myeloid DCs-1 in 38 HIV-1-infected patients with impaired restoration of CD4 T cell counts despite prolonged suppression of plasma viremia (discordant) and compared them with 42 patients showing good immunological and virological responses following highly active antiretroviral therapy (HAART). While myeloid DCs showed spontaneous recovery following HAART in both the groups, the discordant patients demonstrated poor peripheral reconstitution of PDCs as compared with concordant patients. The ability of PDCs to produce IFN-α following stimulation with TLR7 ligand imiquimod and TLR9 ligand CpG ODN-2216 was also impaired in discordant patients even after 2 years following initiation of HAART. Lower IFN-α expression in the PDCs following TLR stimulation was further associated with lower expression of transcription factor, IFN regulatory factor-7. In contrast, production of TNF-α and IL-6 following TLR stimulation was comparable in both groups of patients, indicating that impaired reconstitution characteristics do not affect the capacity of PDCs to produce proinflammatory cytokines. The discordant patients had significantly lower baseline CD4 T cell counts and higher baseline viral load at the initiation of HAART implying that lower baseline CD4 T cell counts and higher plasma viral load are associated with impaired restoration of CD4 T cells and PDCs, thus, increasing the susceptibility of discordant patients toward opportunistic infections despite virological control.

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Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR 7 agonists

Cited by 67 publications

References 115 publications

TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells

Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-α but Not Proinflammatory Cytokines

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