Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy
| العنوان: | Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy |
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| المؤلفون: | Jabir, Majid Sakhi, Hopkins, Lee, Ritchie, Neil D, Ullah, Ihsan, Bayes, Hannah K, Li, Dong, Tourlomousis, Panagiotis, Lupton, Alison, Puleston, Daniel, Simon, Anna Katharina, Bryant, Clare, Evans, Thomas J |
| المساهمون: | Tourlomousis, Panagiotis [0000-0002-6152-8066], Bryant, Clare [0000-0002-2924-0038], Apollo - University of Cambridge Repository |
| المصدر: | Autophagy |
| بيانات النشر: | Taylor & Francis, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | TUBB5, tubulin, β 5 class I, Inflammasomes, ATG, autophagy related, NAC, N-acetylcysteine, NLR proteins, T3SS, type III secretion system, BMDM, bone marrow-derived macrophages, IL1B, interleukin 1, β, BrdU, 5-bromo-2-deoxyuridine, CASP, caspase, GFP, green fluorescent protein, DNA detection, TNF, tumor necrosis factor, LDH, lactate dehydrogenase, Three-MA, 3-methyladenine, Mitophagy, Vav, vav 1 oncogene, LC3B, microtubule-associated protein 1 light chain 3 β, Basic Research Paper, NGS, normal goat serum, Mitochondria, DNA-Binding Proteins, PINK1, PTEN induced putative kinase 1, Pseudomonas aeruginosa, LPS, lipopolysaccharide, Female, ATPIF1, ATPase inhibitory factor 1, Protein Binding, AIM2, absent in melanoma 2, MT-CO1, mitochondrially encoded cytochrome c oxidase I, BID, BH3 interacting domain death agonist, PBS, phosphate-buffered saline, Down-Regulation, Bone Marrow Cells, DNA, Mitochondrial, Autophagy, Animals, Humans, Pseudomonas Infections, Mito-TEMPO, (2-(2, 2, 6, 6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride, Macrophages, NLRC4, NLR family, CARD domain containing 4, Calcium-Binding Proteins, NAIP, NLR family apoptosis inhibitor, Rn18s, 18S rRNA, infection, type III secretion system, mtDNA, mitochondrial DNA, Mice, Inbred C57BL, HEK293 Cells, NLRP3, NLR family, pyrin domain containing 3, Apoptosis Regulatory Proteins, Reactive Oxygen Species, NLR, nucleotide-binding domain, leucine-rich repeat containing |
| الوصف: | The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1554-8635 1554-8627 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::198c2bf672233a0e82f9bd64bbfa097bTest http://europepmc.org/articles/PMC4502769Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....198c2bf672233a0e82f9bd64bbfa097b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548635 15548627 |
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