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Oxidative Stress-initiated One-carbon Metabolism drives Interleukin-10-producing B Cells to Resolute Pneumonia (ATAC-Seq)

ABSTRACT: Metabolic reprogramming for regulatory B cell generation in infectious diseases remains unknown. With a Pseudomonas aeruginosa-induced pneumonia model, we report IL-10-producing B cells (IL-10+B cells) are indispensable for spontaneous remission of the infection. The accumulation of cytosolic reactive oxygen species (ROS) is responsible for the IL-10 producing within B cells. Of note, ROS scavenging downregulated the one-carbon metabolism and the depletion of one-carbon metabolic methyl transfer enzyme serine hydroxymethyl transferase 1 (Shmt1) led to decreased IL-10+ B cells production both in vitro and in vivo. Mechanistically, one-carbon flux enhanced the availability of methyl groups, which altered histone H3 lysine 4 methylation at Il10 loci and led to massive IL-10 production in B cells. Therefore, the metabolic-associated drug ethacrynic acid (EA) was screened out and potentially restored infectious pneumonia accompanied by increased IL-10+ B cells. The results provide a new insight that ROS serve as modulators to resolute inflammation by reprogramming one-carbon metabolism in lung B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE211326 | GEO | 2024/01/03

REPOSITORIES: GEO

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Project description:N-nitroso compounds (NOC) may be implicated in human colon carcinogenesis, but the toxicological mechanisms involved have not been elucidated. Since it was previously demonstrated that nitrosamines and nitrosamides, representing two classes of NOC, induce distinct gene expression effects in colon cells that are particularly related to oxidative stress, we hypothesized that different radical mechanisms are involved. Using ESR spectroscopy, we investigated radical generating properties of genotoxic NOC concentrations in human colon adenocarcinoma cells (Caco-2). Cells were exposed to nitrosamides (N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosurea) or nitrosamines (N-nitrosodiethylamine, N-nitrosodimethylamine, N-nitrosopiperidine, N-nitrosopyrrolidine). Nitrosamines caused formation of reactive oxygen species (ROS) and carbon centered radicals which was further stimulated in presence of Caco-2 cells. N-methyl-N-nitrosurea exposure resulted in a small ROS signal, and formation of nitrogen centered radicals (NCR), also stimulated by Caco-2 cells. N-methyl-N'-nitro-N-nitrosoguanidine did not cause radical formation at genotoxic concentrations, but at increased exposure levels, both ROS and NCR formation was observed. By associating gene expression patterns with ROS formation, several cellular processes responding to nitrosamine exposure were identified, including apoptosis, cell cycle blockage, DNA repair and oxidative stress. These findings suggest that following NOC exposure in Caco-2 cells, ROS formation plays an important role in deregulation of gene expression patterns which may be relevant for the process of chemical carcinogenesis in the human colon, in addition to the role of DNA alkylation. Keywords: Nitrosamines, nitrosamides, N-nitroso compounds, free radicals, toxicogenomics, colon carcinogenesis The study investigated differential gene expression in Caco-2 cell line mRNA following 1, 6 or 24 hours of exposure to six different N-nitroso compounds. Two biological replicates per sample compound. One compound per array, hybridized against vehicle control. Dye-swap between biological replicates.

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Oxidative Stress-initiated One-carbon Metabolism drives Interleukin-10-producing B Cells to Resolute Pneumonia (ATAC-Seq)

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