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The responses against sepsis induced by subcutaneous implantation of the Pseudomonas-contaminated catheters in cGAS-deficient (cGAS\u2212\/\u2212) 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\u2212\/\u2212 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\u2212\/\u2212 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\u2212\/\u2212 macrophages, as indicated by supernatant cytokines, pro-inflammatory molecules (nuclear factor kappa B; NF-\u03baB), M1 polarization (IL-1\u03b2, 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\u2212\/\u2212 macrophages than WT were demonstrated in mice (catheter-induced sepsis and LPS injection model) and in vitro (transcriptomic analysis, macrophage polarization, and METs).<\/jats:p>","DOI":"10.3390\/ijms26115069","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T20:26:50Z","timestamp":1748204810000},"page":"5069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cyclic GMP-AMP Synthase (cGAS) Deletion Promotes Less Prominent Inflammatory Macrophages and Sepsis Severity in Catheter-Induced Infection and LPS Injection Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Chatsuree","family":"Suksamai","sequence":"first","affiliation":[{"name":"Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warerat","family":"Kaewduangduen","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pornpimol","family":"Phuengmaung","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kritsanawan","family":"Sae-Khow","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4375-2141","authenticated-orcid":false,"given":"Awirut","family":"Charoensappakit","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwasin","family":"Udomkarnjananun","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-3039","authenticated-orcid":false,"given":"Sutada","family":"Lotinun","sequence":"additional","affiliation":[{"name":"Center of Excellence in Skeletal Disorders and Enzyme Reaction Mechanism, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3581-7013","authenticated-orcid":false,"given":"Patipark","family":"Kueanjinda","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5566-6403","authenticated-orcid":false,"given":"Asada","family":"Leelahavanichkul","sequence":"additional","affiliation":[{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pinitchun, C., Panpetch, W., Bhunyakarnjanarat, T., Udompornpitak, K., Do, H.T., Visitchanakun, P., Wannigama, D.L., Udomkarnjananun, S., Sukprasansap, M., and Tencomnao, T. 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