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Activation of TLR-like pathways in cDCs involving TRIF and the type I IFNs leads to a protective adaptive response against influenza infection

ABSTRACT: Transcriptomic analyses of rASP-1-activated human blood cDCs revealed that rASP-1 induces upregulation of genes associated with DC maturation, type I IFN and type II IFN signaling involving the TLR4-TRIF transcript components. This transcriptome data in conjunction with the mouse in vitro and and in vivo data suggest the role of TRIF and type I IFNs as critical players in the mechanism of rASP-1 in eliciting a protective response against influenza infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196923 | GEO | 2022/08/12

REPOSITORIES: GEO

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Macrophages from Rosa26-integrated Cas9-expressing C57BL/6 mice have a putative TRIF-mediated defect in the TLR-3/4 signaling

Project description:In this study, we report that the TLR4 ligand, LPS, and TLR3 ligand polyinosinic:polycytidylic acid failed to activate IRF3 or STAT1 in bone marrow–derived macrophages (BMMs) isolated from two independently generated lines of Rosa26-integrated Cas9-expressing C57BL/6J (B6) mice. RNA-sequencing analysis reveals that hundreds to thousands of genes including IFN-stimulated genes were differentially expressed in BMMs from these Cas9 strains compared with B6 upon LPS stimulation. Furthermore, the NF-kB signaling axis and TRIF-mediated necroptosis were also strongly reduced in response to LPS and polyinosinic:polycytidylic acid. In contrast, there were no defects in the responses of BMMs to ligands of the RIG-I, STING, TLR2, TLR9, and IFN receptors. Defects in TLR3 and TLR4 signaling were observed in mice with the B6 but not 129 background, and when Cas9 was integrated at the Rosa26 but not H11 locus. However, integration at the Rosa26 site, CAG promoter–driven Cas9 or eGFP were not individually sufficient to cause the defect. Taken together, the results of this study suggest a putative TRIF-mediated defect in TLR-3/4 signaling in BMMs from commercially available and widely used B6–Cas9–expressing mice. ImmunoHorizons, 2021, 5: 818–829.

2021-09-27 | GSE184551 | GEO

Role of the TRIF-IFN-I pathway in Helicobacter-induced gastric cancer progression in an accelerated murine disease model

Project description:Background: Helicobacter pylori (H. pylori) infection is a known cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the underlying mechanism(s)by which H. pylori infection triggers these disorders are still not clearly understood. Methods: We have developed an accelerated disease progression mouse model, which leverages mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) infected with Helicobacter felis (H. felis) Findings: In this study, we found that H. felis-induced inflammation in Myd88-/- mice progressed to high-grade dysplasia, driven by activation of the type I interferon (IFN-I) signaling pathway and upregulation of its downstream targets, IFN-stimulated genes (ISGs). We also observed enrichment of IFN stimulated-response element (ISRE) motifs in the promoters of upregulated genes, further supporting the involvement of this pathway. In contrast, mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF, TrifLps2) did not progress to severe gastric pathology after H. felis infection, implicating the TRIF signaling pathway in disease pathogenesis and progression. Additionally, analysis of gastric biopsy samples from human gastric cancer patients illustrated that low expression of Myd88 and high expression of Trif were both significantly correlated with poor survival. Interpretation: Our study using an accelerated animal model for gastric cancer and gastric biopsy samples from patients demonstrated that activation of the TRIF-IFN-I signaling pathway promotes Helicobacter-induced disease progression toward severe gastric pathology and gastric cancer development. This represents a potential target for therapeutic intervention, and further exploration may lead to the identification of novel treatment strategies.

2024-04-17 | GSE250438 | GEO

In vitro responses of PBMC and fibroblasts from patients with TRIF deficiency after TRIF dependent and independent stimuli

Project description:We report here unrelated HSE patients with autosomal recessive (AR) or autosomal dominant (AD) TRIF deficiency. The AR form of the disease is due to a homozygous nonsense mutation, resulting in a complete absence of the TRIF protein. Both the TLR3 and the TRIF-dependent TLR4 signaling pathways are abolished. The AD form of TRIF deficiency is due to a heterozygous missense mutation resulting in a dysfunctional protein. The TLR3 signaling pathway is impaired, whereas the TRIF-dependent TLR4 pathway is unaffected. Both patients however showed reduced capacity to respond to cytosolic double stranded RNA, consistent with recent reports of TRIF’s involvement in the DExD/H-box helicases pathway. Skin fibroblast cell lines were derived from healthy controls (n=3), patient with deficiencies for TRIF (n=1), MYD88 (n=1), and TLR3 (n=1) and cultured for 4 hours in the presence of IL1B (20ng/ml) or poly I:C (25ng/ml) or left unstimulated for the same length of time. PBMCs (previously frozen) collected from a healthy control (n=1) and patients with deficiencies for TRIF (n=1), and MYD88 (n=1) were cultured together with LPS (10ng/ml) or R848 (3ug/ml) for 2hrs or left unstimulated for the same length of time.

2011-10-19 | E-GEOD-32390 | biostudies-arrayexpress

In vitro responses of PBMC and fibroblasts from patients with TRIF deficiency after TRIF dependent and independent stimuli

2011-10-20 | GSE32390 | GEO

Sequential MAVS- and MyD88/TRIF-signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes

Project description:Upon tick borne encephalitis virus exposure of brain-resident cells, astrocytes are important IFN-β producers that followed a biphasic response, which initially depends on MAVS- and later on MyD88/TRIF-signaling

2021-09-28 | GSE175823 | GEO

Extracellular vesicles (EV) from IFNγ-primed cardiosphere-derived cells (CDCs)

Project description:Characterization of proteins in extracellular vesicles (EV) from cardiosphere-derived cells (CDCs) of a clinically relevant pig model. Additionally, considering that priming stem cells with inflammatory stimuli may increase the therapeutic potential of released vesicles, here we studied the dynamic changes that take place in the EV from IFNγ-primed CDCs.

2020-05-15 | PXD016434 | Pride

Transcription profiling of mouse LPS-stimulated macrophages from wild-type, MyD88-/- and TRIF-/- animals

Project description:Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand, activates intracellular signaling via adaptors, MyD88 and TRIF, leading to the expression of various genes including proinflammatory cytokines. We used microarrays to examine influence of MyD88 or TRIF deficiency in LPS-inducible gene expression. Experiment Overall Design: Peritoneal macrophages from wild-type, MyD88-/- and TRIF-/- mice were stimulated with LPS for 0, 1 and 4 hours, followed by RNA extraction. Then hybridization on affymetrix microarrays was performed.

2009-03-01 | E-GEOD-14890 | biostudies-arrayexpress

Single-cell RNA-seq reveals heterogeneity within human pre-cDCs

Project description:Here, we use a microfluidics-based approach to prepare single-cell RNA-Seq libraries from 164 primary human conventional dendritic cells (cDCs) as well as cord blood (452) and blood (341) pre-cDCs. We examined heterogeneity between individual cells to document potential subpopulations within human cDCs and pre-cDCs.

2016-11-15 | GSE89232 | GEO

A TLR- and non-TLR-mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade

Project description:Lentiviral vector (LV)-mediated gene transfer is a promising method of gene therapy. We previously reported that systemic injection of LV triggers a transient inflammatory response. Here, we carried out studies to better characterize this response, and to develop a strategy to overcome the effects of interferon (IFN) on LV-mediated gene transfer. We profiled gene expression in the liver after LV administration using deep-sequencing, and identified several innate response pathways. We examined the response to LV in MyD88-TRIF knock-out mice, which are incapable of toll-like receptor (TLR) signaling. The IFN response to LV was not reduced in the liver, indicating that a non-TLR pathway can recognize LV in this tissue. Indeed, blocking reverse-transcription with AZT reduced the IFN response only in the liver, suggesting that proviral DNA can be a trigger. To block the inflammatory response, we pre-treated mice with a short-course of dexamethasone. At 4 hours post-treatment, all of the IFN-induced genes were normalized. By blocking the inflammatory response, hepatocyte transduction was dramatically increased, which doubled the level of human factor-IX produced by a hepatocyte-specific LV. Our studies uncover new insights into LV-induced immune responses in the liver, and provide a means to increase the safety and efficiency of LV-mediated gene transfer. mRNA profiles from livers of untreated and LV-treated mice were generated by deep-sequencing in Illumina HiSeq 2000.

2013-07-05 | E-GEOD-39129 | biostudies-arrayexpress

Expression data of LPS-stimulated macrophages from wild-type, MyD88-/- and TRIF-/- mice.

2009-02-19 | GSE14890 | GEO

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