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LPS-induced TIR domain complex acetylation activated TLR4/MAL/MyD88 signal pathway in sepsis [RNA-Seq]

ABSTRACT: Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE268405 | GEO | 2024/08/01

REPOSITORIES: GEO

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LPS-induced TIR domain complex acetylation activated TLR4/MAL/MyD88 signal pathway in sepsis

Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.

2024-08-01 | PXD052433 | Pride

LPS-induced TIR domain complex acetylation activated TLR4/MAL/MyD88 signal pathway in sepsis [scRNA-Seq]

2024-08-01 | GSE268406 | GEO

A novel treatment for glioblastoma based on Taxol activation of PC1/3-depleted macrophages: evidence from a proteomic and functional study.

Project description:Tumor-associated macrophages contribute to tumor pathogenesis and represent an attractive therapeutic target. We report that the proprotein convertase PC1/3 inhibits the TLR4 Myd88-pathway induced in macrophages by the anti-cancer agent Taxol. Thus, PC1/3 knock-down in these cells exacerbates the TLR4 MyD88-dependent pathway triggered by Taxol. In PC1/3 knock-down macrophages, Taxol drives the secretion of pro-inflammatory cytokines, inhibits STAT3 signaling and counteracts tumor-supportive activities, thus inhibiting viability, growth and invasion of glioblastoma cells. Proteomic analyses indicate that their secretomes are characterized by a unique protein profile supporting a specific paracrine anti-tumoral effect. These findings unravel the potential value of a new therapeutic strategy combining PC1/3 inhibition and activation of the TLR4 MyD88-dependent pathway to switch intra-tumoral macrophages toward an anti-tumoral immunophenotype.

2018-03-19 | PXD004444 | Pride

Sensing prokaryotic mRNA signifies microbial viability and promotes immunity

Project description:MyD88-independent signal transduction associated with Toll-like receptors (TLRs) 3 and TLR4 is mediated through the adapter protein TRIF (TIR-domain-containing adapter-inducing interferon-beta). It has been proposed that TLR signalling is important for the transcription of crucial inflammasome components like NLRP3, a process that has been termed "priming". In order to test whether TRIF signalling was required for the priming of inflammasome components, we performed a genome wide transcriptional analysis on wild-type and Trif-knockout bone marrow derived macrophages (BMMs) before and 1, 3 and 6 hours after phagocytosis of E. coli. These results indicated that TRIF was involved in the activation and not transcriptional priming of the NLRP3 inflammasome. Bone marrow derived macrophages from WT and Trif knockout mice, stimulated with E.coli for up to 6hrs.

2011-05-22 | E-GEOD-27960 | biostudies-arrayexpress

SARS-CoV-2 spike protein interacts with and activates TLR4

Project description:We here identified that the trimeric spike protein of SARS-CoV-2 could bind to TLR4 directly and robustly activate downstream signaling in monocytes and neutrophils. Moreover, specific TLR4 or NFKB inhibitor, or knockout of MyD88 could significantly block IL-1B induction by spike protein. We thus reveal that spike protein of SARS-CoV-2 functions as a potent stimulus causing TLR4 activation and sepsis related abnormal responses.

2021-02-25 | GSE167480 | GEO

C56BL6 WT or MyD88KO BMDM stimulated with different TLRs (part-IV)

Project description:WT control or MyD88 deficient bone marrow derived macrophages were stimulated with TLR2, TLR3, TLR4, TLR7, and TLR9 ligands for 48 h.

2020-04-01 | ST001344 | MetabolomicsWorkbench

Sensing prokaryotic mRNA signifies microbial viability and promotes immunity

2011-05-22 | GSE27960 | GEO

The Second Generation of CAR-iMACs with Enhanced Polarization, CAR-mediated Efferocytosis and Superior Potency against Solid Tumors

Project description:Chimeric antigen receptor (CAR)-T cell therapies have shown great success in treating hematologic malignancies. Nonetheless, their therapeutic effect on solid tumors remains to be improved. Recently, macrophages have attracted great attention, given their ability to infiltrate solid tumors, phagocytize tumor cells as well as their immunomodulatory capacities. The first generation of CD3ζ-based CAR-macrophages demonstrated that the CAR could stimulate macrophage phagocytosis in a tumor antigen-dependent way. Here, we genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) with TLR4 intracellular TIR domain-containing CARs against EGFRvIII and GPC3, which yielded markedly enhanced antitumor effect in two different solid tumor models including glioblastoma, and hepatocellular carcinoma in which complete remission was achieved with CAR-iMACs alone or in combination with CD47 antibody. Moreover, the tandem CD3ζ-TIR-CAR, or the “second-generation” design of TIR-based dual signaling CAR, endowed iMACs with both target engulfment/efferocytosis capacity against antigen-expressing solid tumor cells, and potency of antigen-dependent M1 state polarization and M2 state resistance in an NF-κB dependent manner. We also illustrated a surprising mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we established the next generation CAR-iMACs equipped with orthogonal phagocytosis and polarization capacity for better antitumor functions in treating solid tumors.

2023-09-29 | GSE214140 | GEO

Cross-linking mass spectrometry identifies interacting regions between VACV A46 and human MAL or MyD88

Project description:Vaccinia virus immunomodulator A46 is a member of the poxviral Bcl-2-like protein family that inhibits the cellular innate immune response at the level of the TIR domain-containing TLR adaptor proteins MAL, MyD88, TRAM and TRIF. The mechanism of interaction of A46 with its targets has remained unclear. We used BS3 and EDC + sulfo-NHS to cross-link A46 to the TIR domains of MAL and MyD88 to help identify interacting residues and regions.

2020-10-02 | PXD018786 | Pride

Disabled-2 is a negative immune regulator of lipopolysaccharide-stimulated Toll-like receptor 4 internalization and signaling

Project description:Toll-like receptor 4 (TLR4) plays a pivotal role in the host response to lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Here we elucidated whether the endocytic adaptor protein Disabled-2 (Dab2) that is abundantly expressed in the macrophages plays a role in LPS-stimulated TLR4 signaling and trafficking. Molecular analysis and transcriptome profiling of the RAW264.7 macrophage-like cells expressing short-hairpin RNA of Dab2 revealed that Dab2 mainly regulated LPS-stimulated TRIF-dependent, but not MyD88-dependent TLR4 signaling. Consequently, knockdown of Dab2 augmented TRIF-dependent interferon regulatory factor 3 activation and the expression for the subsets of inflammatory cytokines and interferon-inducible genes. We further delineated that Dab2 acted as a “clathrin sponge” and sequestered clathrin from TLR4/MD2 complex in the resting stage of macrophages. Clathrin was released from Dab2 and associated with TLR4 to facilitate the internalization of TLR4/MD2 complex together with the bound ligand from the cell surface upon LPS stimulation. Dab2 thereby functions as a negative immune regulator of TLR4 endocytosis and signaling, supporting a novel role of Dab2-associated regulatory circuit in the control of inflammatory response of macrophage to endotoxin.

2017-02-09 | GSE81088 | GEO

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