Lipid droplet-mediated danger signaling balances Trem2+ macrophage induction and NLRP3 inflammasome activation in NASH
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA962145 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24318116_1.fastq.gz | Fastqsanger.gz | |||
| SRR24318116_2.fastq.gz | Fastqsanger.gz | |||
| SRR24318117_1.fastq.gz | Fastqsanger.gz | |||
| SRR24318117_2.fastq.gz | Fastqsanger.gz | |||
| SRR24318118_1.fastq.gz | Fastqsanger.gz |
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Project description:Macrophages are exquisitely capable of sensing danger-associated molecular patterns (DAMPs) and orchestrating inflammatory response during tissue injury. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of metabolic fatty liver disease that increases the risk for cirrhosis and liver cancer. Pathogenic mechanisms of NASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. However, the nature of DAMPs released by injured hepatocytes and how they shape the liver immune milieu remain largely unknown. Here we show that lipid droplets (LDs) released by injured fatty hepatocytes provide a potent signal that triggers monocyte infiltration and maturation into Trem2+ macrophages, recently described as NASH-associated macrophages (NAMs) or lipid- associated macrophages. LD treatment exacerbated liver injury in mice with diet-induced NASH. We identified Membrane spanning 4-domains a7 (Ms4a7) as a NAM-specific pathogenic factor that was strongly induced in mouse and human NASH. Ms4a7 inactivation ameliorated key aspects of diet-induced NASH pathologies in mice. At the mechanistic level, Ms4a7 physically interacts with NLR family pyrin domain containing 3 (NLRP3) and is required for endosomal NLRP3 inflammasome activation. These findings illustrate a crucial role of Ms4a7 in driving pro-inflammatory signaling in NASH liver. Surprisingly, LD treatments attenuated Ms4a7 expression and NLRP3 inflammasome activation in cultured macrophages. As such, LDs serve as a DAMP signal that balances the induction of Trem2+ macrophages and NLRP3 inflammasome activation in NASH liver
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Project description:Short chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of the CFLAR and IL10 genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1b release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
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Project description:Short chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of the CFLAR and IL10 genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1b release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation.
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