Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice
| Autor: | Patcharee Ritprajak, Awirut Chareonsappakit, Paweena Susantitaphong, Natavudh Townamchai, Warerat Kaewduangduen, Asada Leelahavanichkul, Peerapat Visitchanakun, Prapaporn Pisitkun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Male LPS Lipopolysaccharide QH301-705.5 Spleen Severity of Illness Index Catalysis Article Proinflammatory cytokine Inorganic Chemistry Sepsis sepsis Mice chemistry.chemical_compound Nucleotidases medicine Extracellular Animals Physical and Theoretical Chemistry Biology (General) Receptor Cecum Molecular Biology QD1-999 Spectroscopy Cyclic GMP-AMP synthase cell free DNA Tumor Necrosis Factor-alpha Macrophages Organic Chemistry cecal ligation and puncture DNA General Medicine medicine.disease Nucleotidyltransferases Molecular biology Interleukin-10 Computer Science Applications Mice Inbred C57BL Chemistry medicine.anatomical_structure Liver chemistry Apoptosis Cytokines Nucleotides Cyclic cGAS |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 11450, p 11450 (2021) Volume 22 Issue 21 |
| ISSN: | 1422-0067 |
| Popis: | Although the enhanced responses against serum cell-free DNA (cfDNA) in cases of sepsis—a life-threatening organ dysfunction due to systemic infection—are understood, the influence of the cytosolic DNA receptor cGAS (cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase) on sepsis is still unclear. Here, experiments on cGAS deficient (cGAS-/-) mice were conducted using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models and macrophages. Severity of CLP in cGAS-/- mice was less severe than in wildtype (WT) mice, as indicated by mortality, serum LPS, cfDNA, leukopenia, cytokines (TNF-α, IL-6 and IL-10), organ histology (lung, liver and kidney) and spleen apoptosis. With the LPS injection model, serum cytokines in cGAS-/- mice were lower than in WT mice, despite the similar serum cfDNA level. Likewise, in LPS-activated WT macrophages, the expression of several mitochondria-associated genes (as revealed by RNA sequencing analysis) and a profound reduction in mitochondrial parameters, including maximal respiration (determined by extracellular flux analysis), DNA (mtDNA) and mitochondrial abundance (revealed by fluorescent staining), were demonstrated. These data implied the impact of cfDNA resulting from LPS-induced cell injury. In parallel, an additive effect of bacterial DNA on LPS, seen in comparison with LPS alone, was demonstrated in WT macrophages, but not in cGAS-/- cells, as indicated by supernatant cytokines (TNF-α and IL-6), M1 proinflammatory polarization (iNOS and IL-1β), cGAS, IFN-γ and supernatant cyclic GMP–AMP (cGAMP). In conclusion, cGAS activation by cfDNA from hosts (especially mtDNA) and bacteria was found to induce an additive proinflammatory effect on LPS-activated macrophages which was perhaps responsible for the more pronounced sepsis hyperinflammation observed in WT mice compared with the cGAS-/- group. |
| Databáze: | OpenAIRE |
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