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Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration

Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP–AMP synthase (cGAS) can recognize fragmented DNA a...

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Autores principales: Suksawad, Nattavong, Udompornpitak, Kanyarat, Thawinpipat, Natchapon, Korwattanamongkol, Pichaya, Visitchanakun, Peerapat, Phuengmaung, Pornpimol, Saisorn, Wilasinee, Kueanjinda, Patipark, Leelahavanichkul, Asada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136362/
https://www.ncbi.nlm.nih.gov/pubmed/37189826
http://dx.doi.org/10.3390/biomedicines11041208
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author Suksawad, Nattavong
Udompornpitak, Kanyarat
Thawinpipat, Natchapon
Korwattanamongkol, Pichaya
Visitchanakun, Peerapat
Phuengmaung, Pornpimol
Saisorn, Wilasinee
Kueanjinda, Patipark
Leelahavanichkul, Asada
author_facet Suksawad, Nattavong
Udompornpitak, Kanyarat
Thawinpipat, Natchapon
Korwattanamongkol, Pichaya
Visitchanakun, Peerapat
Phuengmaung, Pornpimol
Saisorn, Wilasinee
Kueanjinda, Patipark
Leelahavanichkul, Asada
author_sort Suksawad, Nattavong
collection PubMed
description Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP–AMP synthase (cGAS) can recognize fragmented DNA and induce cGAMP synthesis for the activation of the stimulator of interferon genes (STING) pathway. To study the effect of cGAS in uremia-induced systemic inflammation, we performed bilateral nephrectomy (BNx) in wild-type and cGAS knock-out mice and found that the gut leakage and blood uremia from both groups were similar. However, serum cytokines (TNF-α and IL-6) and neutrophil extracellular traps (NETs) decreased significantly in cGAS(−/−) neutrophils after stimulation with LPS or bacterial cell-free DNA. Transcriptomic analysis of LPS-stimulated cGAS(−/−) neutrophils also confirmed the down-regulation of neutrophil effector functions. The extracellular flux analysis showed that cGAS(−/−) neutrophils exhibited a higher respiratory rate than wild-type neutrophils despite having similar mitochondrial abundance and function. Our results suggest that cGAS may control effector functions and the mitochondrial respiration of neutrophils in response to LPS or bacterial DNA.
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spelling pubmed-101363622023-04-28 Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration Suksawad, Nattavong Udompornpitak, Kanyarat Thawinpipat, Natchapon Korwattanamongkol, Pichaya Visitchanakun, Peerapat Phuengmaung, Pornpimol Saisorn, Wilasinee Kueanjinda, Patipark Leelahavanichkul, Asada Biomedicines Article Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP–AMP synthase (cGAS) can recognize fragmented DNA and induce cGAMP synthesis for the activation of the stimulator of interferon genes (STING) pathway. To study the effect of cGAS in uremia-induced systemic inflammation, we performed bilateral nephrectomy (BNx) in wild-type and cGAS knock-out mice and found that the gut leakage and blood uremia from both groups were similar. However, serum cytokines (TNF-α and IL-6) and neutrophil extracellular traps (NETs) decreased significantly in cGAS(−/−) neutrophils after stimulation with LPS or bacterial cell-free DNA. Transcriptomic analysis of LPS-stimulated cGAS(−/−) neutrophils also confirmed the down-regulation of neutrophil effector functions. The extracellular flux analysis showed that cGAS(−/−) neutrophils exhibited a higher respiratory rate than wild-type neutrophils despite having similar mitochondrial abundance and function. Our results suggest that cGAS may control effector functions and the mitochondrial respiration of neutrophils in response to LPS or bacterial DNA. MDPI 2023-04-18 /pmc/articles/PMC10136362/ /pubmed/37189826 http://dx.doi.org/10.3390/biomedicines11041208 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suksawad, Nattavong
Udompornpitak, Kanyarat
Thawinpipat, Natchapon
Korwattanamongkol, Pichaya
Visitchanakun, Peerapat
Phuengmaung, Pornpimol
Saisorn, Wilasinee
Kueanjinda, Patipark
Leelahavanichkul, Asada
Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title_full Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title_fullStr Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title_full_unstemmed Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title_short Cyclic GMP–AMP Synthase (cGAS) Deletion Reduces Severity in Bilateral Nephrectomy Mice through Changes in Neutrophil Extracellular Traps and Mitochondrial Respiration
title_sort cyclic gmp–amp synthase (cgas) deletion reduces severity in bilateral nephrectomy mice through changes in neutrophil extracellular traps and mitochondrial respiration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136362/
https://www.ncbi.nlm.nih.gov/pubmed/37189826
http://dx.doi.org/10.3390/biomedicines11041208
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