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Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.

ABSTRACT: Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response in a minipig lung I/R injury model. Left lung I/R injury triggered inflammatory cytokine production and activated the autophagy flux as evidenced in crude lung tissues and alveolar macrophages. This was associated with the release of DAMPs, such as high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60). Indeed, treatment with recombinant HMGB1 or HSP60 induced autophagy in alveolar macrophages, whereas autophagy inhibition by knockdown of ATG7 or BECN1 markedly reduced DAMP-triggered production of inflammatory cytokines including IL-1?, TNF and IL12 in alveolar macrophages. This appeared to be because of decreased activation of MAPK and NF-?B signaling. Furthermore, knockdown of ATG7 or BECN1 inhibited Lys63 (K63)-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) in DAMP-treated alveolar macrophages. Consistently, treatment with 3-MA inhibited K63-linked ubiquitination of TRAF6 in I/R-injured lung tissues in vivo. Collectively, these results indicate that autophagy triggered by DAMPs during lung I/R injury amplifies the inflammatory response through enhancing K63-linked ubiquitination of TRAF6 and activation of the downstream MAPK and NF-?B signaling.

SUBMITTER: Liu X

PROVIDER: S-EPMC5384028 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.

Liu Xingguang X Cao Hao H Li Jian J Wang Bo B Zhang Peng P Dong Zhang Xu X Liu Zhongmin Z Yuan Hongbin H Zhan Zhenzhen Z

Cell death and differentiation 20170203 4

Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response ...[more]

PMID: 28157209

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Project description:BackgroundAcute kidney injury (AKI) is a common complication in patients, especially elderly patients, who undergo cardiac surgery with cardiopulmonary bypass. Studies have indicated a protective role of autophagy in AKI. However, the mechanisms underlying the regulatory effect of autophagy in AKI among patients undergoing cardiac surgeries are poorly understood. In this study, we aimed to test the hypothesis that exosomal microRNAs (miRNAs) regulate autophagy in tubular epithelial cells after AKI.MethodsPlasma exosomal RNA was extracted from young and elderly AKI patients undergoing cardiac surgery, and the miRNAs expression during the perioperative period were analyzed using next-generation sequencing. The screened miRNAs and their target genes were subjected to gene oncology function and Kyoto Encyclopedia of Genes and Genome enrichment analyses. Renal tubular epithelial cell line (HK-2 cells) was cultured and hypoxia/reoxygenation (H/R) model was established, which is an in vitro renal ischemia/reperfusion (I/R) model. We used Western blot analysis, cell viability assay, transfection, luciferase assay to investigate the mechanisms underlying the observed increases in the levels of renal I/R injury-mediated exosomal miRNAs and their roles in regulating HK-2 cells autophagy.ResultsmiR-590-3p was highly enriched in the plasma exosomes of young AKI patients after cardiac surgery. Increased levels of miR-590-3p led to the increases in the expression of autophagy marker proteins, including Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3II), and prolonged the autophagic response in HK-2 cells after H/R treatment. These effects were achieved mainly via increases in the exosomal miR-590-3p levels, and the tumor necrosis factor receptor-associated factor 6 protein was shown to play a key role in I/R injury-mediated autophagy induction.ConclusionExosomes released from HK-2 cells after renal I/R injury regulate autophagy by transferring miR-590-3p in a paracrine manner, which suggests that increasing the miR-590-3p levels in HK-2 cell-derived exosomes may increase autophagy and protect against kidney injury after renal I/R injury.

Dataset Information

Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.

Publications

Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.

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