Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect

Figure 7

Schematic representation showing the mechanism of cigarette smoke-induced exacerbations in COPD via TFEB-mediated autophagy impairment. Our mechanistic analysis shows that CS/ROS exposure causes TFEB accumulation in aggresome bodies, thus impairing expression of autophagy-regulating proteins leading to chronic autophagy inhibition. Furthermore, CS exposure also causes a decrease in CFTR membrane expression, due to its similar accumulation in aggresome bodies further aggravating autophagy. This CS-mediated chronic autophagy impairment induces a phagocytic defect that results in an increase in bacterial infection as a mechanism for recurring or chronic exacerbations in COPD-emphysema subjects. Moreover, treatment with over-the-counter antioxidant medication, fisetin that induces TFEB expression to restore levels of autophagy proteins, corrects the CS-induced phagocytic defect. Thus, suggesting therapeutic potential of fisetin or autophagy-inducing drugs in controlling recurrent exacerbations in COPD-emphysema subjects.