TMAO promoted TREM-1 expression through NLRP3 inflammasome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250419 | GEO | 2023/12/18
REPOSITORIES: GEO
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Project description:Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Mice were treated with TMAO in normal saline by oral gavage for 14 consecutive days. Then, mice were made into MCAO models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in stroke, microglia of MCAO mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Our results demonstrated that TMAO promoted the release of inflammatory cytokines in the brain of MCAO mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3, TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in stroke through FTO/IGF2BP2.
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Project description:Purpose: The goals of this study were to identify preferential gene expression signatures that are unique to HAECs stimulated with the uremic toxin, TMAO, to accelerate vascular inflammation associated with chronic kidney diseases. Methods and results: HAECs were treated with TMAO (600 µM) for 18 hours, and RNAs were collected to generate mRNA transcription profiles. Transcriptional profiling revealed a unique TMAO stimulated HAECs relative to a non-stimulated control HAECs. Conclusion: Our study represents the first detailed analysis of TMAO treated HAECs transcriptome.
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Project description:Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counter-acted the suppressive effect of TMAO on megalin expression. Our results may further help us un-ravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
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Project description:The activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but the precise roles of lysosomes are still unclear. Here we show the vital role of the Ragulator complex, a lysosomal protein, in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophage and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed remarkable attenuation of the severity of NLRP3-associated inflammatory diseases, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with histone deacetylase 6 (HDAC6) during NLRP3 inflammasome activation, and this interaction augmented the interaction between the Ragulator complex and NLRP3. Lack of HDAC6 attenuated the interaction between Lamtor1 and NLRP3, resulting in insufficient NLRP3 inflammasome activation. Furthermore, DL-all-rac-α-tocopherol inhibited Lamtor1–HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. Our results provide insight into the role of lysosomes in providing a platform for the activation of NLRP3 inflammasomes by the Ragulator complex.
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Project description:Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3-ASC complex formation, ASC oligomerization, caspase-1 activation, and IL-1β and IL-18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3-associated inflammatory diseases, including MSU- and Alum-induced peritonitis and LPS-induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation-dependent manner, subsequently recruiting the BRISC to remove K63-linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active component of BRISC, displays similar phenotypes to ABRO1 knockout mice. Our findings reveal an ABRO1-mediated regulatory signaling system that controls activation of the NLRP3 inflammasome and provide novel potential targets for treating NLRP3-associated inflammatory diseases.
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Project description:Gene expression levels after TMAO treatment
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