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Article

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

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Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, Chulalongkorn University, Bangkok 10330, Thailand
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Nephrology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Research Unit for Metabolic Bone Disease in CKD Patients, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10330, Thailand
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Research Unit in Integrative Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
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Renal Immunology and Renal Transplant Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Authors to whom correspondence should be addressed.
Academic Editors: Malgorzata Kloc and Jacek Z Kubiak
Int. J. Mol. Sci. 2021, 22(21), 11450; https://doi.org/10.3390/ijms222111450
Received: 22 September 2021 / Revised: 14 October 2021 / Accepted: 14 October 2021 / Published: 23 October 2021
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. View Full-Text
Keywords: sepsis; cell free DNA; LPS; cGAS; cecal ligation and puncture sepsis; cell free DNA; LPS; cGAS; cecal ligation and puncture
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MDPI and ACS Style

Visitchanakun, P.; Kaewduangduen, W.; Chareonsappakit, A.; Susantitaphong, P.; Pisitkun, P.; Ritprajak, P.; Townamchai, N.; Leelahavanichkul, A. Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice. Int. J. Mol. Sci. 2021, 22, 11450. https://doi.org/10.3390/ijms222111450

AMA Style

Visitchanakun P, Kaewduangduen W, Chareonsappakit A, Susantitaphong P, Pisitkun P, Ritprajak P, Townamchai N, Leelahavanichkul A. Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice. International Journal of Molecular Sciences. 2021; 22(21):11450. https://doi.org/10.3390/ijms222111450

Chicago/Turabian Style

Visitchanakun, Peerapat, Warerat Kaewduangduen, Awirut Chareonsappakit, Paweena Susantitaphong, Prapaporn Pisitkun, Patcharee Ritprajak, Natavudh Townamchai, and Asada Leelahavanichkul. 2021. "Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice" International Journal of Molecular Sciences 22, no. 21: 11450. https://doi.org/10.3390/ijms222111450

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