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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32390 | GEO | 2011/10/20

SECONDARY ACCESSION(S): PRJNA147937

REPOSITORIES: GEO

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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

Complete TLR3 deficiency

Project description:The objective of this study is to study the Toll-like receptor 3 (TLR3)-dependent gene expression in human fibroblast cells and peripheral blood mononuclear cells (PBMCs) Fibroblast cells and PBMCs from donors with autosomal recessive (AR) complete TLR3 deficiency and autosomal dominant (AD) partial TLR3 deficiency were collected for microarray analysis to measure the transcriptional responsiveness of TLR3 in fibroblast and PBMCs. A total of 3 healthy controls, 1 AD TLR3-deficient patient, 1 AR TLR3-deficient patient, 1 AR UNC-93B-deficient patient, 1 MyD88 deficient patien were used in this study. The fibroblast cells were cultured in DMEM medium supplemented with 10% fetal calf serum (FCS). The PBMCs were cultured in RPMI medium complemented with 10% FCS. Different kinetics (2 hours and 8 hours) of poly(I:C) (25ug/ml, purchased from Amersham) stimulations were performed, aiming to define TLR3-inducible genes in these human cells. A stimulation of IL-1β (20ng/ml, purchased from R&D system Inc.) was used as a positive activation control with same kinetics of stimulations. A total of one million cells per stimulation were used for fibroblasts, and around 1.5 million cells per stimulation for PBMCs.

2011-11-02 | E-GEOD-30951 | biostudies-arrayexpress

A Population of Radio-Resistant Macrophages in the Deep Myenteric Plexus Contributes to Postoperative Ileus Via Toll-Like Receptor 3 Signaling

Project description:Postoperative ileus (POI) is triggered by an innate immune response in the muscularis externa (ME) and is accompanied by bacterial translocation. Bacteria can trigger an innate immune response via toll-like receptor (TLR) activation, but the latter’s contribution to POI has been disproved for several TLRs, including TLR2 and TLR4. Herein we investigated the role of double-stranded RNA detection via TLR3 and TIR-domain-containing adapter inducing interferon-b (TRIF) signaling pathway in POI. POI was induced by small bowel intestinal manipulation in wt, TRIF-/-, TLR3-/-, type I interferon receptor-/- and interferon-b reporter mice, all on C57BL/6 background, and POI severity was quantified by gene expression analysis, gastrointestinal transit, and leukocyte extravasation into the ME. TRIF/ TLR3 deficiency reduced postoperative ME inflammation and prevented POI. With bone marrow transplantation, RNA-sequencing, flow cytometry, and immunohistochemistry we revealed a distinct TLR3-expressing radio-resistant MHCIIhiCX3CR1- IBA-1+ resident macrophage population within the deep myenteric plexus. TLR3 deficiency in these cells, but not in MHCIIhiCX3CR1+ macrophages, reduced cytokine expression in POI. While this might not be an exclusive macrophage-privileged pathway, the TLR3/TRIF axis contributes to proinflammatory cytokine production in MHCIIhiCX3CR1- IBA-1+ macrophages during POI. Deficiency in TLR3/TRIF protects mice from POI. These data suggest that TLR3 antagonism may prevent POI in humans.

2022-02-21 | GSE132147 | GEO

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

ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

Project description:Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl, and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many mucosal epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl. Intriguingly, expression of ZBP1 was elevated in Casp8-/- Tnfr1-/- embryos prior to their succumbing to aberrant necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because rare Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. Of note, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5-7 weeks of being born, which is not seen in Casp8-/- Ripk1-/- Trif-/- Zbp1-/-, Casp8-/- Ripk3-/-, or Casp8-/- Mlkl-/- mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.

2024-04-01 | GSE254754 | GEO

In vitro responses of fibroblasts from patients with TBK1 deficiency after TLR3 dependent and independent stimuli

Project description:We report here two unrelated HSE patients carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function, but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal dominant (AD) trait, but by different mechanisms: haplotype-insufficiency (D50A) or negative dominance (G159A). A defect in poly(I:C)-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A, but not for D50A TBK1. Skin fibroblast cell lines were derived from healthy controls (n=3), patients with deficiencies for TBK1 (n=2), TLR3 (n=2), STAT1 (n=1) and cultured for 2 or 8 hours in the presence of IFNa (105 IU/ml), IL1b (20ng/ml), or poly I:C (25ug/ml) or left unstimulated for the same length of time.

2012-07-29 | E-GEOD-38652 | biostudies-arrayexpress

In vitro responses of fibroblasts from patients with TBK1 deficiency after TLR3 dependent and independent stimuli

2012-07-30 | GSE38652 | GEO

C56BL6 WT or TRIFKO BMDM stimulated with different TLRs (part-III)

Project description:WT control or TRIF deficient bone marrow derived macrophages were stimulated with TLR2, TLR3, and TLR4 ligands for 48 h.

2020-04-01 | ST001343 | MetabolomicsWorkbench

N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization

Project description:Many immune responses depend upon activation of NF-κB, a key transcription factor in the elicitation of a cytokine response. Here we show that N4BP1 inhibits TLR-dependent activation of NF-κB by interacting with the NF-κB signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like (ubiquitin conjugation to ER degradation) domains in N4BP1 mediate the interaction with the NEMO COZI domain. Both in vitro and in mice, N4bp1 deficiency specifically enhances TRIF-independent (TLR2, TLR7, or TLR9-mediated), but not TRIF-dependent (TLR3 or TLR4-mediated), NF-κB activation leading to increased production of proinflammatory cytokines. In response to TLR4 or TLR3 activation, TRIF causes activation of caspase-8, which cleaves N4BP1 distal to residues D424 and D490 and abolishes its inhibitory effect. N4bp1-/- mice also exhibit diminished numbers of T cells in the peripheral blood. Our work identifies N4BP1 as an inhibitory checkpoint protein that must be overcome to activate NF-κB, and a TRIF-initiated caspase-8-dependent mechanism by which this is accomplished.

2021-02-08 | GSE165916 | GEO

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

Project description: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.

2022-08-12 | GSE196923 | GEO

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