Autophagy plays an essential role in the clearance of <i>Pseudomonas aeruginosa</i> by alveolar macrophages

Yuan, Kefei; Huang, Canhua; Fox, John; Laturnus, Donna I.; Carlson, Edward C.; Zhang, Binjie; Yin, Qi; Gao, Hongwei; Wu, Min

doi:10.1242/jcs.094573

Cited by 155 publications

(190 citation statements)

References 49 publications

Supporting

Mentioning

183

Contrasting

Order By: Relevance

“…3,4,18,19 Infection with this bacterium also initiates autophagy. 17,20 We found that inhibition of autophagy upregulated inflammasome activation following P. aeruginosa infection. This was due to autophagy removing damaged mitochondria that released mitochondrial DNA following infection in a process dependent on production of reactive oxygen intermediates.…”

Section: Introductionmentioning

confidence: 92%

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Jabir¹,

Hopkins²,

Ritchie³

et al. 2015

Autophagy

146

112

View full text Add to dashboard Cite

Abbreviations: Three-MA, 3-methyladenine; AIM2, absent in melanoma 2; ATG, autophagy related; ATPIF1, ATPase inhibitory factor 1; BID, BH3 interacting domain death agonist; BMDM, bone marrow-derived macrophages; BrdU, 5-bromo-2-deoxyuridine; CASP, caspase; GFP, green fluorescent protein; IL1B, interleukin 1, b; LC3B, microtubule-associated protein 1 light chain 3 b; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; Mito-TEMPO, (2-(2, 2, 6, 6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride; MT-CO1, mitochondrially encoded cytochrome c oxidase I; mtDNA, mitochondrial DNA; NAC, N-acetylcysteine; NAIP, NLR family apoptosis inhibitor; NGS, normal goat serum; NLR, nucleotide-binding domain, leucine-rich repeat containing; NLRC4, NLR family, CARD domain containing 4; NLRP3, NLR family, pyrin domain containing 3; PBS, phosphate-buffered saline; PINK1, PTEN induced putative kinase 1; Rn18s, 18S rRNA; T3SS, type III secretion system; TNF, tumor necrosis factor; TUBB5, tubulin, b 5 class I; Vav, vav 1 oncogene.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.

show abstract

Section: Introductionmentioning

confidence: 92%

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Jabir¹,

Hopkins²,

Ritchie³

et al. 2015

Autophagy

146

112

View full text Add to dashboard Cite

show abstract

“…Autophagy or autophagic protein exerts its role in host defense by degrading various clinically important pathogens in the lysosome. The target pathogens include bacteria such as Mycobacterium tuberculosis (35), Pseudomonas aeruginosa (194), group A Streptococcus pyogens (119), Shigella flexneri (117), Salmonella enterica (19,185), and Listeria monocytogenes (196), virus such as herpes simplex virus type 1 (HSV-1) (191), and parasites such as Toxoplasma gondii (196).…”

Section: Role Of Autophagy In Microbial Clearancementioning

confidence: 99%

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Nakahira

Cloonan

Mizumura

et al. 2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Autophagy is a fundamental cellular process that functions in the turnover of subcellular organelles and protein. Activation of autophagy may represent a cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Autophagy can increase survival during nutrient deficiency and play a multifunctional role in host defense, by promoting pathogen clearance and modulating innate and adaptive immune responses. Recent Advances: Autophagy has been described as an inducible response to oxidative stress. Once believed to represent a random process, recent studies have defined selective mechanisms for cargo assimilation into autophagosomes. Such mechanisms may provide for protein aggregate detoxification and mitochondrial homeostasis during oxidative stress. Although long studied as a cellular phenomenon, recent advances implicate autophagy as a component of human diseases. Altered autophagy phenotypes have been observed in various human diseases, including lung diseases such as chronic obstructive lung disease, cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis. Critical Issues: Although autophagy can represent a pro-survival process, in particular, during nutrient starvation, its role in disease pathogenesis may be multifunctional and complex. The relationship of autophagy to programmed cell death pathways is incompletely defined and varies with model system. Future Directions: Activation or inhibition of autophagy may be used to alter the progression of human diseases. Further resolution of the mechanisms by which autophagy impacts the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid. Redox Signal. 20,

show abstract

“…Finally, the autophagosome fuses with the lysosome, forming an autolysosome, where the cargo is digested by lysosomal enzymes and the degraded material released into the cytoplasm for recycling by the cell. macrophages and their response to different stimuli, 22,24,25 thus highlighting the connections among autophagy, macrophages, and cancer, and suggesting the potential to enhance an antitumor response by modulating autophagy in macrophages. Given the major roles of macrophages and autophagy in tumor progression and their correlation in biological activities, it is valuable to clarify the contribution and underlying molecular mechanisms of autophagy-mediated regulation of macrophages, and their implications for cancer.…”

Section: Introductionmentioning

confidence: 99%

Autophagy-mediated regulation of macrophages and its applications for cancer

2013

View full text Add to dashboard Cite

Autophagy plays an essential role in the clearance of Pseudomonas aeruginosa by alveolar macrophages

Cited by 155 publications

References 49 publications

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Autophagy-mediated regulation of macrophages and its applications for cancer

Contact Info

Product

Resources

About