Role of autophagy in lung diseases and ageing

Abstract

The lungs face ongoing chemical, mechanical, biological, immunological and xenobiotic stresses over a lifetime. Advancing age progressively impairs lung function. Autophagy is a "housekeeping" survival strategy involved in numerous physiological and pathological processes in all eukaryotic cells. Autophagic activity decreases with age in several species, whereas its basic activity extends throughout the lifespan of most animals. Dysregulation of autophagy has been proven to be closely related to the pathogenesis of several ageing-related pulmonary diseases. This review summarises the role of autophagy in the pathogenesis of pulmonary diseases associated with or occurring in the context of ageing, including acute lung injury, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis, and describes its potential as a therapeutic target.

FIGURE 1

Illustration of autophagy. Autophagy involves the formation of autophagosomes and their fusion with lysosomes to form autolysosomes. The process is typically divided into distinct stages: initiation, elongation/closure and autophagosome–lysosome fusion. Initiation begins with activation of the complex. Unc-51-like autophagy activating kinase 1 (ULK1) and Atg13 are key to the ULK1 complex and are further supported by Atg101 and FAK family-interacting protein of 200 kDa (FIP200). Mammalian target of rapamycin complex 1 (mTORC1) binds to ULK1 and inhibits the ULK1 complex, and 5ʹ AMP-activated protein kinase (AMPK) phosphorylates mTORC1, resulting in the dissociation of mTORC1 from ULK. The ULK1 complex activates a class III PI3K complex consisting of VPS34, VPS15, Beclin-1 and Atg14L and activates the molecule in BECN1-regulated autophagy protein 1 (AMBRA1). The phagophore elongates and encloses to a double-membrane autophagosome. This step is tightly regulated via the ubiquitin-like conjugation systems. For example, the Atg12–Atg5:Atg16L1 complex conjugates phosphoethanolamine to LC3 to LC3-II, and LC3-II promotes substrate uptake upon binding to different receptors, such as p62. The autophagosome fuses with a lysosome to form an autolysosome for degradation. The inner content is released into the lysosome/autolysosome and is degraded by lysosomal hydrolases. The SNARE-like proteins may play critical roles in autophagosome–lysosome degradation. LAMP1: lysosomal-associated membrane protein 1.

FIGURE 2

The crosstalk of autophagy with endoplasmic reticulum (ER) stress and apoptosis. ER stress activates autophagy to promote cell survival. Autophagy is transcriptionally regulated by acting transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP) and can oppose terminal unfolded protein response and ATF4. CHOP regulates numerous Atg. ER stress activates c-Jun NH2-terminal kinase (JNK) via the interaction of inositol-requiring enzyme 1α (IRE1α) and TNF receptor-associated factor 2 (TRAF2), ultimately phosphorylating Bcl-2 and leading to dissociation of Bcl-2 and Beclin-1 proteins. This enables the activation of the PI3K complex and initiates autophagy. ER-stress-induced activation of apoptosis requires IRE1α. IRE1α forms a complex with apoptosis signal-regulating kinase 1 (ASK1) and stimulates its downstream target, JNK, via binding to TRAF2. ER-stress-induced apoptosis via a caspase-dependent pathway. ER stress leads to the translocation of Bcl-2-like protein 11 (BIM) to the ER, leading to caspase-12 activation. Caspase-12 activates caspase-9, leading to downstream caspase-3 activation in this cascade, finally triggering apoptosis. Additionally, IRE1α causes the phosphorylation and activation of CHOP through binding and activation of p38 mitogen-activated protein kinase (MAPK). CHOP downregulates Bcl-2 and upregulates the transcription of BIM, eventually causing the downstream initiation of an apoptotic cascade. PERK: protein kinase RNA-like ER kinase.

FIGURE 3

Multiple mechanisms contributing to inflammaging and the involvement of autophagy. Multiple mechanisms contribute to inflammaging, eventually leading to lung pathogenesis. Senescence in immune and nonimmune cells increases inflammatory mediator release via the release of senescence-associated secretory phenotype (SASP). In aged intestines, dysbiosis of intestinal microbiota and a decreased intestinal barrier allow bacterial products to translocate to the circulatory system, where they trigger low systemic inflammation. Damaged and/or dead cells and organelles act as damage-associated molecular patterns (DAMPs) to activate an auto-inflammatory response by binding to pattern recognition receptors (PRRs) on innate immune cells. Age-related declines in autophagy and macrophage phagocytic activity also contribute to DAMP accumulation and lead to inflammation and ageing. Autophagy promotes recycling cellular content, generating nutrients and energy to maintain homeostasis, preventing recognition of pathogen-associated molecular patterns by PRRs and inflammation. Autophagy can also control inflammation via the regulation of innate immunity signalling by removing endogenous inflammasome agonists and through its effects on immune mediator secretion. Additionally, autophagy modulates innate immunity, antigen presentation and T-cell function. Furthermore, mitophagy inhibits mitochondrial DNA (mtDNA) accumulation and excessive mitochondrial reactive oxygen species (ROS) production, both of which may accelerate cellular senescence and aggravate the inflammaging process. IL-1β: interleukin 1 beta.