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

2019 ◽  
Vol 20 (4) ◽  
pp. 895 ◽  
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.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

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.

scholarly journals Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Kunli Zhang ◽  
Sutian Wang ◽  
Hongchao Gou ◽  
Jianfeng Zhang ◽  
Chunling Li
Keyword(s):  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Degradation Process ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Research Progress ◽  
Type I ◽  
Type I Ifn ◽  
Major Pathway ◽  
Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

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

2010 ◽  
Vol 184 (7) ◽  
pp. 3341-3345 ◽  
Author(s):  
Katsuaki Hoshino ◽  
Izumi Sasaki ◽  
Takahiro Sugiyama ◽  
Takahiro Yano ◽  
Chihiro Yamazaki ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Cutting Edge ◽  
Type I ◽  
Type I Ifn ◽  
Iκb Kinase

Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3263-3271 ◽  
Author(s):  
Maria Montoya ◽  
Giovanna Schiavoni ◽  
Fabrizio Mattei ◽  
Ion Gresser ◽  
Filippo Belardelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

Abstract Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-α and IFN-β, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti–IFN-α/β antibody to purified splenic DCs in vitro partially blocked the “spontaneous” activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-γ, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Defense Mechanism ◽  
Histopathological Examination ◽  
Bacterial Count ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR was performed to detect the expression of Type I IFNs and related genes. M. bovis induced lung lesions were assessed by histopathological examination and viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell recruitment and activation in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals When Dendritic Cells Go Viral: The Role of Siglec-1 in Host Defense and Dissemination of Enveloped Viruses

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 8 ◽  
Author(s):  
Daniel Perez-Zsolt ◽  
Javier Martinez-Picado ◽  
Nuria Izquierdo-Useros
Keyword(s):  
Dendritic Cells ◽  
Sialic Acid ◽  
Cell Activation ◽  
Type I Interferons ◽  
Lymphoid Tissues ◽  
Type I ◽  
Dissemination Strategy ◽  
Enveloped Viruses ◽  
Viral Spread

Dendritic cells (DCs) are among the first cells that recognize incoming viruses at the mucosal portals of entry. Initial interaction between DCs and viruses facilitates cell activation and migration to secondary lymphoid tissues, where these antigen presenting cells (APCs) prime specific adaptive immune responses. Some viruses, however, have evolved strategies to subvert the migratory capacity of DCs as a way to disseminate infection systemically. Here we focus on the role of Siglec-1, a sialic acid-binding type I lectin receptor potently upregulated by type I interferons on DCs, that acts as a double edge sword, containing viral replication through the induction of antiviral immunity, but also favoring viral spread within tissues. Such is the case for distant enveloped viruses like human immunodeficiency virus (HIV)-1 or Ebola virus (EBOV), which incorporate sialic acid-containing gangliosides on their viral membrane and are effectively recognized by Siglec-1. Here we review how Siglec-1 is highly induced on the surface of human DCs upon viral infection, the way this impacts different antigen presentation pathways, and how enveloped viruses have evolved to exploit these APC functions as a potent dissemination strategy in different anatomical compartments.

The Role of the Cytoplasmic RNA Sensor Retinoic Acid Inducible Gene- I (RIG-I) in Allogeneic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3827-3827
Author(s):  
Julius Clemens Fischer ◽  
Caroline A Lindemans ◽  
Chia-Ching Lin ◽  
Alexander Wintges ◽  
Michael Bscheider ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Stem Cell ◽  
Retinoic Acid ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Epithelial Regeneration ◽  
Inflammatory Bowel ◽  
Inducible Gene

Abstract The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute graft-versus-host disease (GVHD). Improving the procedure depends on identifying the mechanisms that contribute to this damaging T cell reactivity, while preserving graft-versus-leukemia (GVL) activity against hematopoietic malignancies. "Tonic" type I IFN signaling in BMT recipients and therapeutic application of recombinant IFN-α have been shown to play an important role in defining the balance between GVHD and GVL responses, but the molecular mechanisms inducing this protective response remains unknown. In this regard, pattern recognition receptors (PRRs) that detect cytosolic nucleic acids and lead to the production of large amounts of type I interferons (IFN-α/β) such as the family of RIG-I-like receptors (RLRs) are of particular interest. RLRs, a subfamily of the cytoplasmic DExD/H- box family of helicases, consist of three members: retinoic acid inducible gene I (RIG-I), melanoma differentiation factor 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I senses viral and bacterial RNA to induce the production of type I interferons, proinflammatory cytokines and inflammasome activation. Double-stranded RNA (dsRNA) carrying a 5'-triphosphate (3pRNA) has been identified as the natural ligand for RIG-I and serves as a selective trigger for RIG-I signaling. Although initially characterized as a main regulator for antiviral host defense, mice deficient in components of the RLR and type I IFN signaling pathway develop inflammatory bowel disease (IBD)-related pathologies. Furthermore, patients suffering from IBD show a highly significant downregulation of RIG-I in ileal epithelial cells and in a recent meta-analysis of genome-wide association studies (GWAS) data, IFNAR1 and MDA-5 were identified as primary candidate genes in susceptible loci for IBD. Together, these results indicate that RLRs and type I IFN signaling have important functions in the suppression of IBD by yet ill defined mechanisms. Given that the pathophysiology of GVHD shares several features with inflammatory bowel disease (IBD), we tested the role of the RIG-I pathway in the context of allo-HSCT. We utilized MAVS-deficient mice, which lack a common adapter for RIG-I signaling, as recipients in an MHC-disparate (BALB/c into B6) model of allo-HSCT. Compared to wild-type (WT) B6 mice, MAVS-KO mice receiving allogeneic BM + T cells displayed significantly worse GVHD mortality (Fig.1 A). Given the enhanced GVHD observed in the absence of RIG-I signaling, we hypothesized that selective engagement of RIG-I by 3pRNA (RIG-I ligand) in vivo would protect recipients from GVHD. Using a B6 into BALB/c model we observed that i.v. administration of a selective RIG-I ligand on d-1 significantly reduced mortality, weight loss and intestinal GVHD histopathology (Fig. 1B and data not shown). In addition, the translocation of LPS and microorganisms from the bowel lumen through the damaged intestinal mucosa to the systemic circulation during pre-transplant conditioning represents a crucial step in GVHD pathophysiology. We observed that administration of RIG-I ligand prior to allo-HSCT augmented intestinal barrier function measured by less fluorescence in the serum after FITC-dextran gavage compared to untreated WT recipients (Fig. 1C). Moreover, RIG-I stimulation augmented epithelial regeneration as determined by organoid formation from freshly isolated crypts (Fig. 1D) and inhibited activation of dendritic cells (DCs) during pre-transplant conditioning (Fig. 1E). To investigate the impact of 3pRNA administration during GVT, we used luciferase+ A20 bioluminescence in B6 into BALB/c tumor challenge recipients demonstrating that RIG-I ligands do not limit GVL (data not shown). Taken together, our results (i) uncover a previously unknown role of the RIG-I-MAVS signaling pathway in GVHD and (ii) offer a novel strategy to foster epithelial regeneration and inhibit antigen presentation during pre-transplant conditioning, while maintaining GVL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effective Chemokine Secretion by Dendritic Cells and Expansion of Cross-Presenting CD4−/CD8+ Dendritic Cells Define a Protective Phenotype in the Mouse Model of Coxsackievirus Myocarditis

2008 ◽  
Vol 82 (16) ◽  
pp. 8149-8160 ◽  
Author(s):  
Andreas Oliver Weinzierl ◽  
Gudrun Szalay ◽  
Hartwig Wolburg ◽  
Martina Sauter ◽  
Hans-Georg Rammensee ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myocarditis ◽  
Type I Interferons ◽  
Mouse Strains ◽  
Type I ◽  
Necrosis Factor Alpha ◽  
Chronic Myocarditis ◽  
Cvb3 Infection

ABSTRACT Enteroviruses such as coxsackievirus B3 (CVB3) are able to induce lethal acute and chronic myocarditis. In resistant C57BL/6 mice, CVB3 myocarditis is abrogated by T-cell-dependent mechanisms, whereas major histocompatibility complex (MHC)-matched permissive A.BY/SnJ mice develop chronic myocarditis based on virus persistence. To define the role of T-cell-priming dendritic cells (DCs) in the outcome of CVB3 myocarditis, DCs were analyzed in this animal model in the course of CVB3 infection. In both mouse strains, DCs were found to be infectible with CVB3; however, formation of infectious virions was impaired. In DCs derived from C57BL/6 mice, significantly higher quantities of interleukin-10 (IL-10) and the proinflammatory cytokines IL-6 and tumor necrosis factor alpha were measured compared to those from A.BY/SnJ mice. Additionally, the chemokines interferon-inducible protein 10 (IP-10) and RANTES were secreted by DCs from resistant C57BL/6 mice earlier in infection and at significantly higher levels. The protective role of IP-10 in CVB3 myocarditis was confirmed in IP-10−/− mice, which had increased myocardial injury compared to the immunocompetent control animals. Also, major differences in resistant and permissive mice were found in DC subsets, with C57BL/6 mice harboring more cross-priming CD4− CD8+ DCs. As CD4− CD8+ DCs are known to express 10 times more Toll-like receptor 3 (TLR3) than other DC subsets, we followed the course of CVB3 infection in TLR3−/− mice. These mice developed a fulminant acute myocarditis and secreted sustained low amounts of type I interferons; secretion of IP-10 and RANTES was nearly abrogated in DCs. We conclude that MHC-independent genetic factors involving DC-related IP-10 secretion and TLR3 expression are beneficial in the prevention of chronic coxsackievirus myocarditis.

scholarly journals The Yin and Yang of Type I IFNs in Cancer Promotion and Immune Activation

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 856
Author(s):  
Martina Musella ◽  
Claudia Galassi ◽  
Nicoletta Manduca ◽  
Antonella Sistigu
Keyword(s):  
Deep Understanding ◽  
Type I Interferons ◽  
Host Immune System ◽  
Type I ◽  
Type I Ifn ◽  
Dual Nature ◽  
Adaptive Resistance ◽  
Type I Ifns ◽  
Yin And Yang

Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.

scholarly journals The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Isaac T. W. Harley ◽  
Timothy B. Niewold ◽  
Rebecca M. Stormont ◽  
Kenneth M. Kaufman ◽  
Stuart B. Glenn ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Systemic Autoimmune Disease ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Genome Wide

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated theIFNKlocus in SLE susceptibility. We studiedIFNKsingle nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93,P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific.IFNKSNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association betweenIFNKSNPs and SLE and skin phenotypes. The serum IFN association suggests thatIFNKvariants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

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