Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia
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Autophagy has emerged as a key regulator of the inflammatory response. To examine the role of autophagy in the development of organ dysfunction during endotoxemia, wild-type and autophagy-deficient (Atg4b-null) mice were challenged with lipopolysaccharide. Animals lacking Atg4b showed increased mortality after endotoxemia. Among the different organs studied, only the lungs showed significant differences between genotypes, with increased damage in mutant animals. Autophagy was activated in lungs from wild-type, LPS-treated mice. Similarly, human bronchial cells show an increased autophagy when exposed to serum from septic patients. We found an increased inflammatory response (increased neutrophilic infiltration, higher levels of Il6, Il12p40, and Cxcl2) in the lungs from knockout mice and identified perinuclear sequestration of the anti-inflammatory transcription factor ATF3 as the putative mechanism responsible for the differences between genotypes. Finally, induction of autophagy by starvation before LPS exposure resulted in a dampened pulmonary response to LPS in wild-type, but not knockout, mice. Similar results were found in human bronchial cells exposed to LPS. Our results demonstrate the central role of autophagy in the regulation of the lung response to endotoxemia and sepsis and its potential modulation by nutrition.
Endotoxemia and sepsis trigger autophagy in lung tissue.
Defective autophagy increases mortality and lung inflammation after endotoxemia.
Impairment of autophagy results is perinuclear ATF3 sequestration.
Starvation ameliorates lung injury by an autophagy-dependent mechanism.
KeywordsAutophagy Lung injury Endotoxemia Sepsis Inflammatory response ATF3 sequestration
The authors thank Carlos López-Otin for his support during the development of the study and Ana Gutierrez-Fernandez for her help with the immunofluorescence studies. They also thank Marta S. Pitiot, Carmen Muñiz and Vanessa García for their help with histological studies. This work was supported by grants from Instituto de Salud Carlos III (FIS-PI 10/606, FEDER funds, INT 12/007 to GMA), Universidad de Oviedo (UNOV 09-pf to AGL), Fundación Universidad de Oviedo (to AA), Asociación Española contra el Cancer (AECC predoctoral grant to ILA), and Fundación para el fomento en Asturias de la investigación científica aplicada y la tecnología (FICYT-COF 11–40 to EBS). Instituto Universitario de Oncología del Principado de Asturias (IUOPA) is supported by Obra Social-Cajastur.
The authors declare no conflict of interest related to this study.
- 3.Gonzalez-Lopez A, Aguirre A, Lopez-Alonso I, Amado L, Astudillo A, Fernandez-Garcia MS, Suarez MF, Batalla-Solis E, Colado E, Albaiceta GM (2012) MMP-8 deficiency increases TLR/RAGE ligands S100A8 and S100A9 and exacerbates lung inflammation during endotoxemia. PLoS ONE 7:e39940PubMedCentralPubMedCrossRefGoogle Scholar
- 8.Lopez-Alonso I, Aguirre A, Gonzalez-Lopez A, Fernandez AF, Amado-Rodriguez L, Astudillo A, Batalla-Solis E, Albaiceta GM (2013) Impairment of autophagy decreases ventilator-induced lung injury by blockade of the NF-kappaB pathway. Am J Physiol Lung Cell Mol Physiol 304:L844–L852PubMedCrossRefGoogle Scholar
- 13.Gonzalez-Lopez A, Astudillo A, Garcia-Prieto E, Fernandez-Garcia MS, Lopez-Vazquez A, Batalla-Solis E, Taboada F, Fueyo A, Albaiceta GM (2011) Inflammation and matrix remodeling during repair of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 301:L500–L509PubMedCrossRefGoogle Scholar
- 20.Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP et al (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230PubMedCentralPubMedCrossRefGoogle Scholar