Autophagy and Asthma

Asthma is a major cause of ill health worldwide, characterised by a complex, heterogeneous mixture of syndromes that can be subdivided into several phenotypes on the basis of clinical, physiological and inflammatory markers that in turn can result in variable responses to treatment 1, 2. Patients with the severe form of the disease often suffer frequent asthma exacerbations that may require intensive treatment with daily oral corticosteroids in a hospital setting with attendant side effects, quality of life and healthcare costs 3. These patients represent a clear, unmet medical need, representing a major cause of morbidity and mortality and consuming a significant proportion of healthcare resources. Keeping this in view, current research into asthma pathology seeks to identify new pathways involved in pathogenesis to guide the development of therapeutic targets. One such emerging area is autophagy. Autophagy is a highly conserved fundamental evolutionary process that represents a vital homoeostatic cellular waste disposal mechanism whereby ubiquitin-tagged or Hsp-chaperoned, often damaged, cytosolic components or intracellular pathogens are engulfed in autophagosomes and transported to lysosomes for degradation. Autophagy has been shown to be an important regulator in many critical biological processes responsible for protection against cellular stressors with factors such as reactive oxidative stress (ROS), starvation, microbial infection and endoplasmic reticulum stress initiating the autophagy cascade from phagosome formation, fusion with lysosome (autophagosome) and ultimately breakdown of cellular components. Autophagy is also one major mechanism of cell death, but this is not an inevitable process, and in certain circumstances, it can protect against cell death 4. The autophagy pathway has been implicated in processes as diverse as immune dysfunction, the pathogenesis of inflammatory disorders and responses to viral infection. With regard to the latter, a number of studies have examined the contribution of autophagy to replication and immune responses to common respiratory viruses in asthma exacerbations 5. As with apoptosis, autophagy is believed to be a double-edged sword as both excessive and impaired autophagy are associated with diverse diseases 6, 7. Autophagy consists of initiation, execution and maturation, being mediated by an ubiquitination-like system that involves two key pathways 8. In the first, the autophagy gene 12 (Atg12) is activated by transient covalent linkage first to Atg7 and then to Atg10 before covalent linkage to Atg5. Atg16 binding generates an Atg5–Atg12–Atg16 complex that is present in the autophagy isolation membrane. In the second, a terminal amino acid at the C-terminus of microtubule-associated protein light chain 3 (LC3; also known as Atg8) is cleaved by the cysteine protease Atg4, exposing a conserved glycine residue that is required for autophagosome formation. Cleaved LC3 is then transiently linked to Atg7, then to Atg3, and then to phosphatidylethanolamine 9. Apoptosis is a fundamental physiologic mechanism for cell disposal without inflammation that is vital for the maintenance of homoeostasis in the lung, with both positive and negative regulation of apoptosis thought to be critical determinants of the progression of lung disease 10. The role of autophagy in respiratory diseases is attracting increasing interest as the interface between the lungs and the environment leads to exposure to a diverse array of environmental and infectious cellular stressors. Thus, the view that the mitigation of autophagy-mediated cellular stress plays a key regulatory role in lung pathophysiology is an attractive one 11. For example, a number of studies have demonstrated that autophagy may play an important role in the pathogenesis of COPD and idiopathic pulmonary fibrosis 12. The genetic association of autophagy and asthma was examined in two recent studies. The Atg5 gene is located on chromosomal region 6q21 and is approximately 141 kilobase pairs in length. Atg gene variants have been studied, and a single-nucleotide polymorphism (SNP) in Atg5 was found to be related to childhood asthma 13. In adults, 12212740, an intronic SNP of Atg 5, was found to be associated with asthma and pre-bronchodilator percentage forced expiratory volume in 1 second (FEV1) predicted in two asthma cohorts, one in a French Canadian population and another in an American Caucasian cohort. Furthermore, double-membrane autophagosomes were more prevalent in fibroblasts and epithelial cells from a bronchial biopsy tissue of a moderately severe asthmatic patient compared with corresponding cells of a healthy subject 14. The airway epithelium is the first line of defence in the lung and in addition to mucociliary and barrier functions has several innate defence mechanisms, including effectors such as mucins, antimicrobial peptides and reactive oxygen species to entrap or kill invading microbes 15. In addition, airway epithelial cells can connect innate and adaptive immunity by producing cytokines and chemokines that act on diverse immune cells. In asthma, the epithelium exhibits signs of damage with an impaired ability to repair itself with more mucus-producing goblet cells present than in normal airways 16. Thus, the epithelium has the potential to create a microenvironment enabling the deviation of immune and inflammatory responses to external stimuli that may be crucial to asthma development and progression 17. A number of studies suggest that autophagy might play a general role in stress responses in airway epithelial cells. In COPD, autophagosomes and LC3-II levels are higher in lung samples compared with control samples, while either cigarette smoke extract or hyperoxia increased autophagy activity and cilia injury in airway epithelial cells 12. Thus, in epithelial cells autophagy activity may serve as a functional response to noxious or inflammatory signals such as IL-13, a Th2-type pleiotropic cytokine whose levels are increased in both COPD and asthma with important effects on mucus hypersecretion by goblet cells and ROS generation 18. It is of interest therefore that a recent study by Dickinson and colleagues 19 utilised a murine model of airway disease in which IL-33 stimulation resulted in IL-13-dependent formation of airway goblet cells that was attenuated in Atg16l1-deficient mice compared to wild-type control animals. These workers also reported that IL-13 activates autophagy in differentiated human tracheal airway epithelial cells to direct mucin secretion and cell oxidant stress responses. Prolonged exposure of airway epithelial cells to IL-13 promoted increased LC3-II expression relative to actin, indicating increased autophagy activity. Additionally, depleting Atg5 or Atg14 in IL-13-treated airway epithelial cells resulted in goblet cell hypertrophy and a decrease in MUC5AC secretion. Of additional interest was the observation that blocking autophagy in this model significantly attenuated IL-13-mediated ROS generation. ROS is essential as part of normal inflammatory responses, but overproduction of ROS is thought to contribute to asthma pathogenesis as exhaled mediator levels associated with ROS correlate with the severity of asthma symptoms 20. There is also good evidence that IL-13 promotes transforming growth factor-β1 (TGF-β1)-dependent airway remodelling through subepithelial mesenchymal cell proliferation that, along with other pro-inflammatory cells, produces a thickened subepithelial layer that is considered to be a distinct feature of severe asthma. Thus, autophagy may be a cellular mechanism that promotes TGF-β1 airway remodelling and loss of lung function in asthma. Finally, these interesting findings contradict those reported in macrophages where IL-13 has inhibitory effects on starvation-induced autophagy 5. In the current issue, the study by Ban et al. 21 explored the association between asthma severity and autophagy. These researchers used a novel Cyto-IDR fluorescent probe autophagy detection assay to examine autophagy markers in peripheral blood cells, eosinophils and sputum granulocytes in subjects with severe and non-severe asthma compared with healthy controls. There was evidence for autophagy in both eosinophils and airway epithelial cells, and this was modulated by chloroquine and not dexamethasone. As the authors acknowledge, their observations in airway epithelial cells were made in commercially sourced cells and different results may have been observed had cells from their asthmatic subjects been studied. Their findings demonstrated an association between severe asthma and autophagy, although not in patients with non-severe asthma. To what extent do the findings reported in this study support the notion that autophagy and asthma are inter-linked? The findings of the study were consistent with the studies discussed above which do suggest that asthma and autophagy are associated. At present, the findings summarised are supportive of the notion that targeting autophagy in severe asthma may represent a novel therapeutic approach, but clearly our understanding of the mechanistic pathways involved requires clarification in further well-designed studies. Such studies also have the potential to open up a new avenue for the exploration of alternative mechanisms of severe asthma pathogenesis. One potentially exciting approach is the fact that known autophagy inhibitors that are FDA approved for alternative indications are now being studied in clinical trials, primarily as cancer therapeutics 22, 23. Use of these agents may provide a rapid pathway by which to translate such findings into novel treatments that target autophagy in conditions such as asthma, COPD and other chronic lung disease. Overall, this study provided novel insights into an association of autophagy with severe asthma and, as with all good studies, these intriguing findings have opened up some difficult new questions that require to be answered. Conflict of interest: The authors declare no conflict of interest.

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