Jabir, M. et al. (2015) Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. Autophagy, 11(1), pp. 166-182. (doi: 10.4161/15548627.2014.981915) (PMID:25700738) (PMCID:PMC4502769)
|
Text
99815.pdf - Published Version Available under License Creative Commons Attribution Non-commercial. 1MB |
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.
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Ullah, Mr Ihsan and Ritchie, Dr Neil and Bayes, Dr Hannah and Evans, Professor Tom |
Authors: | Jabir, M., Hopkins, L., Ritchie, N., Ullah, I., Bayes, H., Li, D., Tourlomousis, P., Lupton, A., Puleston, D., Simon, A., Bryant, C., and Evans, T. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Autophagy |
Publisher: | Taylor and Francis |
ISSN: | 1554-8627 |
ISSN (Online): | 1554-8635 |
Published Online: | 20 February 2015 |
Copyright Holders: | Copyright © 2015 The Authors |
First Published: | First published in Autophagy 11(1):166-182 |
Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record