Cyclic GMP-AMP Synthase (cGAS) Deletion Promotes Less Prominent Inflammatory Macrophages and Sepsis Severity in Catheter-Induced Infection and LPS Injection Models.

Activation of cGAS, a cytosolic receptor recognizing double-stranded DNA, in macrophages is important in sepsis (a life-threatening condition caused by infection). The responses against sepsis induced by subcutaneous implantation of the -contaminated catheters in cGAS-deficient (cGAS) mice were lower than in wild-type (WT) mice as indicated by liver enzymes, white blood cell count, cytokines, and M1-polarized macrophages in the spleens. Likewise, a lethal dose of lipopolysaccharide (LPS) induced less severe sepsis severity as determined by mortality, organ injury, cell-free DNA, and serum cytokines. Patterns of the transcriptome of lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages were clearly different between cGAS and WT cells. Gene set enrichment analysis (GSEA; a computational statistical determination of the gene set) indicated more prominent enrichment of oxidative phosphorylation (OXPHOS; the mitochondrial function) 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 indicated by supernatant cytokines, pro-inflammatory molecules (nuclear factor kappa B; ), M1 polarization (, CD80, and CD86), and macrophage extracellular traps (METs; web-like structures composed of DNA, histones, and other proteins) through the detection of citrullinated histone 3 (CitH3) in supernatant and immunofluorescent visualization. In conclusion, less prominent pro-inflammatory responses of cGAS macrophages than WT were demonstrated in mice (catheter-induced sepsis and LPS injection model) and in vitro (transcriptomic analysis, macrophage polarization, and METs).