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| Item Type: | Article |
|---|---|
| Title: | Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy |
| Creators Name: | Jabir, M.S., Hopkins, L., Ritchie, N.D., Ullah, I., Bayes, H.K., Li, D., Tourlomousis, P., Lupton, A., Puleston, D., Simon, A.K., Bryant, C. and Evans, T.J. |
| Abstract: | 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. |
| Keywords: | DNA Detection, Infection, Mitophagy, NLR Proteins, Type III Secretion System, Animals, Mice |
| Source: | Autophagy |
| ISSN: | 1554-8627 |
| Publisher: | Taylor & Francis |
| Volume: | 11 |
| Number: | 1 |
| Page Range: | 166-182 |
| Date: | 2015 |
| Additional Information: | Copyright © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC Copyright © Majid Sakhi Jabir, Lee Hopkins, Neil D. Ritchie, Ihsan Ullah, Hannah K. Bayes, Dong Li, Panagiotis Tourlomousis, Alison Lupton, Daniel Puleston, Anna Katharina Simon, Clare Bryant, and Thomas J. Evans This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
| Official Publication: | https://doi.org/10.4161/15548627.2014.981915 |
| PubMed: | View item in PubMed |
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