Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst
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ABSTRACT:
PROVIDER: PRJNA889172 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21855934_1.fastq.gz | Fastqsanger.gz | |||
| SRR21855934_2.fastq.gz | Fastqsanger.gz | |||
| SRR21855935_1.fastq.gz | Fastqsanger.gz | |||
| SRR21855935_2.fastq.gz | Fastqsanger.gz | |||
| SRR21855936_1.fastq.gz | Fastqsanger.gz |
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Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate.
2023-01-01 | GSE215195 | GEO
Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can evade immune clearance. Here, we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects the lung from excessive inflammation but compromises bacterial clearance. S. aureus is thus able to evade the innate immune response by targeting neutrophil metabolism and inducing the production of the anti-inflammatory metabolite itaconate.
| S-EPMC10387506 | biostudies-literature
Project description:Macrophages are involved in the pathophysiology of many diseases as critical cells of the innate immune system. Pyroptosis is a form of macrophage death that induces cytokinesis of phagocytic substances in the macrophages, thereby defending against infection. Dimethyl itaconate (DI) is an analog of itaconic acid with anti-inflammatory effects. However, the effect of dimethyl itaconate on macrophage pyroptosis has not been elucidated clearly. Thus, the present study aimed to analyze the effect of DI treatment on a macrophage pyroptosis model (Lipopolysaccharide, LPS+Adenosine Triphosphate, ATP). The results showed that 0.25 mM DI ameliorated macrophage pyroptosis and downregulated interleukin (IL)-1β expression. Then, real-time quantitative polymerase chain reaction (RT-qPCR) was used to confirm the result of RNA-sequencing of the upregulated oxidative stress-related genes (Gclc and Gss) and downregulated inflammation-related genes (IL-12β and IL-1β). In addition, Gene Ontology (GO) enrichment analysis showed that differential genes were associated with transcript levels and DNA replication. Kyoto encyclopedia of genes and genomes (KEGG) enrichment showed that signaling pathways, such as tumor necrosis factor (TNF), Jak, Toll-like receptor and IL-17, were altered after DI treatment. N-acetyl-L-cysteine (NAC) reversed the DI effect on the LPS+ATP-induced macrophage pyroptosis and upregulated the IL-1β expression. Oxidative stress-related protein Nrf2 is involved in the DI regulation of macrophage pyroptosis. Taken together, these findings suggested that DI alleviates the pyroptosis of macrophages through oxidative stress.
2021-10-16 | GSE185895 | GEO
Project description:Dimethyl Itaconate alleviates the pyroptosis of macrophages through oxidative stress
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Project description:We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcgR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment nor lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.
2024-05-17 | GSE243974 | GEO
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.
2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress
Project description:Neutrophils play a critical role in host defense and sterile inflammation. However, neutrophil dysfunction is a hallmark of the acquired immunodeficiency in kidney disease, contributing to an increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that the impaired renal clearance of the metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-14 mg/dL) related or unrelated to kidney disease significantly exacerbated the inflammatory immune response to infection by impairing neutrophil dynamics and functions in mice with mono- and polybacterial sepsis. This aggravated inflammatory response was partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using either neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restored neutrophil dysfunction. Mechanistically, sUA impaired the phagocytic capability, bacterial clearance, and oxidative burst in neutrophils by modulating cytoskeletal dynamics and promoting degranulation, processes essential for host defense. In contrast, sUA had no impact on neutrophil extracellular trap formation in neutrophils from healthy subjects exposed to LPS or E.coli. Our findings identify HU related or unrelated to kidney disease as immune regulator in exacerbating the inflammatory response during sepsis, primarily by impairing neutrophil-mediated phagocytosis, pathogen clearance, and oxidative burst. Targeting UA may help to overcome the acquired immunodeficiency during infection, while aggravating sterile forms of inflammation.
2026-04-14 | GSE294890 | GEO
Project description:The necrotrophic fungus Botrytis cinerea rapidly kills host tissue with its secreted proteins and metabolites. Necrotrophs can trigger the hypersensitive response (HR), which is accompanied by reactive oxygen species (ROS) production, but it remains unclear whether this ROS burst promotes or restricts B. cinerea infection. We have combined Arabidopsis RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) mutant analysis, luminol-based in vivo assays, and the use of CRISPR-Cas generated B. cinerea ROS detoxification mutants to analyze the toxic effect of the ROS burst. In addition, RNA-sequencing, expression analyses and redox imaging were used to study RBOHD-dependent signaling and redox homeostasis. RBOHD mutants showed increased susceptibility to B. cinerea infection, and the apoplastic ROS burst was dependent on RBOHD. Fungal mutants confirmed the importance of SUPEROXIDE DISMUTASE 1 (SOD1) and ACTIVATOR PROTEIN 1 (AP1) for ROS detoxification and virulence. Unexpectedly, the transcriptomes of B. cinerea-infected Arabidopsis Col-0 and RBOHD mutant were highly similar, providing no evidence for a connection of extracellular ROS production and intracellular ROS-induced transcriptional signaling. Nevertheless, RBOHD activity was found to be involved in the maintenance of cellular redox homeostasis under phytotoxic stress. Our results demonstrate an exclusive and protective role of the RBOHD-dependent oxidative burst, but B. cinerea counteracts this response via different detoxification mechanisms.
2026-01-28 | GSE317547 | GEO
Project description:Bone remodeling is a highly dynamic process dependent on the precise coordination of osteoblasts and hematopoietic-cell derived osteoclasts. Emerging evidence indicates that cellular differentiation is associated with a metabolic rewiring in conjunction with the acquisition of specific effector functions. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. We show that during differentiation preosteoclasts rearrange their tricarboxylic acid (TCA) cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterized by induction of immunoresponsive gene 1 (Irg1) and production of itaconate, which accumulates intra- and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generationin vitroandin vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation, reducing proliferation and shifting ATP production from mitochondrial respiration to glycolysis. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely,Irg1deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognized regulator of the crosstalk between osteoclasts and osteoblasts
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