Investigation of the effect of succinate and dimethyl malonate on murine bone-marrow derived macrophages (BMDMs) treated with or without LPS
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78849 | GEO | 2016/09/27
SECONDARY ACCESSION(S): PRJNA314136
REPOSITORIES: GEO
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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.
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Project description:Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct microenvironment-associated metabolic processes. Here, we identified SDH deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to a wide range of anti-cancer therapies. Mechanistically, succinate promoted the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function was mediated by succinate-triggered upregulation of UBC12 phosphorylation, which impaired its E2 function in cullins neddylation. Notably, decreasing succinate levels by fludarabine could effectively restore the drug sensitivity of SDH-deficient AML PDX. Together, we uncover a novel function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.
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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.
2016-07-01 | GSE82043 | GEO
Project description:we report that succinate, a metabolite abundantly produced by the dysbiotic gut microbiota, induces in vitro biofilm formation of C. difficile strains. We characterized the morphology and spatial composition of succinate- induced biofilms, and compared to non-induced or deoxycholate-induced biofilms, biofilms induced by succinate are significantly thicker, structurally more complex, and poorer in proteins and exopolysaccharides (EPS).
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