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TNF-R1 Co-opts TLR4 Pathway Components CD14, TRAM and TRIF to Drive TNF-Induced Inflammation and Toxicity

ABSTRACT: TNF-R1 Co-opts TLR4 Pathway Components CD14, TRAM and TRIF to Drive TNF-Induced Inflammation and Toxicity

PROVIDER: PRJNA870769 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21120274.fastq.gz	Fastqsanger.gz
	SRR21120275.fastq.gz	Fastqsanger.gz
	SRR21120276.fastq.gz	Fastqsanger.gz
	SRR21120277.fastq.gz	Fastqsanger.gz
	SRR21120278.fastq.gz	Fastqsanger.gz

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TNF-R1 Co-opts TLR4 Pathway Components CD14, TRAM and TRIF to Drive TNF-Induced Inflammation and Toxicity

Project description:We report the application of single-cell-sequencing technology for the profiling of TRIF-dependent changes in immune cell populations, and TRIF-dependent cellular responses in the spleens of mice 4 hours after intravenous injection with recombinant murine TNF.

2022-08-21 | GSE211539 | GEO

SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling in human macrophages.

Project description:Signaling lymphocytic activation molecule family 1 (SLAMF1) is an Ig-like receptor and a costimulatory molecule that initiates signal transduction networks in a variety of immune cells. In this study, we report that SLAMF1 is required for Toll-like receptor 4 (TLR4)-mediated induction of interferon β (IFNβ) and for killing of Gram-negative bacteria by human macrophages. We found that SLAMF1 controls trafficking of the Toll receptor-associated molecule (TRAM) from the endocytic recycling compartment (ERC) to Escherichia coli phagosomes. In resting macrophages, SLAMF1 is localized to ERC, but upon addition of E. coli, it is trafficked together with TRAM from ERC to E. coli phagosomes in a Rab11-dependent manner. We found that endogenous SLAMF1 protein interacted with TRAM and defined key interaction domains as amino acids 68 to 95 of TRAM as well as 15 C-terminal amino acids of SLAMF1. Interestingly, the SLAMF1-TRAM interaction was observed for human but not mouse proteins. Overall, our observations suggest that SLAMF1 is a new target for modulation of TLR4-TRAM-TRIF inflammatory signaling in human cells.

| S-EPMC5881497 | biostudies-literature

Neutrophils and macrophages drive TNF-induced lethality via TRIF/CD14-mediated responses.

Project description:TNF mediates a variety of biological processes including cellular proliferation, inflammatory responses, and cell death and is therefore associated with numerous pathologies including autoinflammatory diseases and septic shock. The inflammatory and cell death responses to TNF have been studied extensively downstream of TNF-R1 and are believed to rely on the formation of proinflammatory complex I and prodeath complex II, respectively. We recently identified a similar multimeric complex downstream of TLR4, termed the TRIFosome, that regulates inflammation and cell death in response to LPS or Yersinia pseudotuberculosis. We present evidence of a role for the TRIFosome downstream of TNF-R1, independent of TLR3 or TLR4 engagement. Specifically, TNF-induced cell death and inflammation in murine macrophages were driven by the TLR4 adaptor TRIF and the LPS co-receptor CD14, highlighting an important role for these proteins beyond TLR-mediated immune responses. Via immunoprecipitation and visualization of TRIF-specific puncta, we demonstrated TRIF- and CD14-dependent formation of prodeath and proinflammatory complexes in response to TNF. Extending these findings, in a murine TNF-induced sepsis model, TRIF and CD14 deficiency decreased systemic inflammation, reduced organ pathology, and improved survival. The outcome of TRIF activation was cell specific, because TNF-induced lethality was mediated by neutrophils and macrophages responding to TNF in a TRIF-dependent manner. Our findings suggest that in addition to their crucial role in TNF production, myeloid cells are central to TNF toxicity and position TRIF and CD14 as universal components of receptor-mediated immune responses.

| S-EPMC10021564 | biostudies-literature

Resolving monocytes generated through TRAM deletion attenuate the pathogenesis of atherosclerosis

Project description:We performed scRNAseq analysis of murine monocytes cultured from bone marrow isolates of WT and TRAM knockout mice. WT and TRAM knockout monocytes were cultured in vitro for 5 days in the presence or absence of low dose LPS (100 pg/ml).

2021-11-10 | GSE182237 | GEO

Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway.

Project description:Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2(-/-) mice were highly susceptible to Gram-negative bacteria-induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro-inflammatory cytokine production (IL-6, TNFα and IL-1β). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage.

| S-EPMC4630631 | biostudies-literature

LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF.

Project description:Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-beta (TRIF)-related adaptor molecule (TRAM) is the fourth TIR domain-containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-kappaB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-alpha/beta, regulated on activation, normal T cell expressed and secreted (RANTES), and gamma interferon-inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor-like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.

| S-EPMC2194210 | biostudies-literature

Monocyte exhaustion mediated by TRAM

Project description:Monocyte exhaustion mediated by TRAM

| PRJNA755992 | ENA

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.

2011-10-20 | GSE32390 | GEO

Generation of resolving neutrophils with 4-PBA or genetic deletion of TRAM

Project description:We have generated resolving neutrophils with anti-inflammatory potency, through applying the pharmacological agent 4-PBA or genetically depleting TRAM molecule. WT murine neutrophils treated with PBS or 4-PBA for overnight were harvested for scRNAseq analysis to examine the generated resolving neutrophil phenotype. In addtion, we have cultured WT and TRAM KO neutrophils and compared the resolving phenotype via scRNAseq analysis.

2022-04-20 | GSE182356 | GEO

Monocyte exhaustion mediated by TRAM

Project description:We performed single cell sequencing analysis of exhausted monocytes generated in vitro through prolonged incubation with high dose LPS. We demonstated that 5-day prolonged stimulation of WT but not TRAM KO monocytes with high dose LPS drastically induced monocyte exhaustion, as reflected in higher levels of inflammatory marker genes such as CD38 and immuno-suppressor genes including PD-L1.

2021-10-22 | GSE182355 | GEO

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