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Cyclic GMP-AMP synthase (cGAS) deletion promotes less prominent inflammatory macrophages and sepsis severity in catheter-induced infection mice

ABSTRACT: Activation of cGAS, a cytosolic DNA receptor, in macrophages might be important in sepsis (a life-threatening condition caused by infection). The severity of sepsis induced by subcutaneous implantation of Pseudomonas-contaminated catheter in cGAS-deficient (cGAS-/-) mice was less severe than in wild-type (WT) as indicated by liver enzymes, total white blood cell count, cytokines, and M1-polarized macrophages in the spleens (flow cytometry analysis), but not bacteremia, endotoxemia, and serum cell-free DNA. Patterns of the transcriptome of lipopolysaccharide (LPS)-stimulated bone marrow-derived mac-rophages were clearly different between cGAS-/- and WT cells. Gene set enrichment analysis (GSEA) indicated more prominent enrichment of oxidative phosphorylation (OXPHOS) and mTORC1 pathways in LPS-activated cGAS-/- macrophages compared with WT. Meanwhile, LPS upregulated cGAS and increased cGAMP (a cGAS inducer) only in WT macrophages along with less severe inflammation in cGAS-/- macrophages, as in-dicated by supernatant cytokines, pro-inflammatory molecules (NF-κB), M1 polarization (IL-1β, CD80, and CD86), and macrophage-extracellular traps (METs) through detection of citrullinated histone 3 (CitH3) in supernatant and in immunofluorescent visualization. In conclusion, less severe inflammatory responses of cGAS-/- macrophages than WT were demonstrated in mice (catheter-induced sepsis) and in vitro (transcriptomic analysis, macrophage polarization, and METs). Further studies using cGAS inhibitors in bacterial sepsis are interesting.

ORGANISM(S): Mus musculus

PROVIDER: GSE284706 | GEO | 2025/03/22

REPOSITORIES: GEO

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Project description:Sensing of microbial products by innate immune cells skew their transcriptional program to optimize anti-microbial defences. Chromatin remodeling by histone deacetylases (HDACs) plays a fundamental role in tailoring gene expression. HDAC inhibitors are among the most promising anti-cancer drugs and possess intrinsic anti-inflammatory properties. Yet, the influence of HDAC inhibition on innate immune responses to microbial infection is unknown. Here we show that HDAC inhibitors repress the expression of less than 10% of the genes expressed at baseline in BM-derived macrophages. In sharp contrast, HDAC inhibitors strongly interfere with transcriptome remodeling induced by LPS and Pam3CSK4, affecting the expression of 30-70% of genes modulated by microbial stimuli. Strikingly, HDAC inhibitors target the expression of numerous genes involved in anti-microbial host defences, encoding for microbial sensors, cytokines, chemokines, growth factors and their receptors, adhesion and signaling molecules, and molecules involved in antigen processing and presentation. At the molecular level, HDAC inhibitors do not impair mitogen-activated protein kinase, NF-kB, interferon-related factor signal and STAT1 transduction pathways, but inhibit NF-kB p65 recruitment to the promoter region of HDAC inhibitor-sensitive genes. HDAC inhibitors also inhibit the response of mouse and human DCs, splenocytes and whole blood to a broad range of microbial products and microorganisms. In agreement with these in vitro findings, HDAC inhibitors increase bacterial burden and sensitize mice to sub-lethal infection with Klebsiella pneumoniae and Candida albicans. Conversely, HDAC inhibitors confer protection in models of Pam3CSK4-induced fulminant toxic shock and severe sepsis following cecal ligation and puncture. Overall, these data substantiate the concept of immunomodulation by HDAC inhibitors, and suggest that these drugs could represent efficacious adjunctive therapy of severe sepsis. Mus musculus cells were grown in presence of LPS or LPS + TSA and pam or pam + TSA and hybrydised against a cRNA pool UMRR (from Mus musculus cells).

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Cyclic GMP-AMP synthase (cGAS) deletion promotes less prominent inflammatory macrophages and sepsis severity in catheter-induced infection mice

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