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Abstract
Insult or injury to the lung epithelial cells from pathogens, pollutants, and allergens can initiate the process of apoptotic cell death. Although "Creola bodies," which are clusters of uncleared, apoptotic, epithelial cells, have been seen in the sputum of patients with asthma, the clearance of these dying epithelial cells and the consequence of failed clearance in the airway have not been directly addressed. We have observed that bronchial epithelial cells efficiently engulf their apoptotic neighbors and produce antiinflammatory cytokines when engulfing apoptotic cells. Furthermore, when the phagocytic capacity of bronchial epithelial cells was impaired, mice developed severe, IL-33-dependent, allergic airway inflammation. This inflammation could be ameliorated by exogenous administration of the antiinflammatory cytokine IL-10. Our data suggest that the process of apoptotic cell engulfment is a mechanism by which bronchial epithelial cells regulate the inflammatory environment within the lung. Collectively, these studies suggest that impaired engulfment pathways in airway epithelial cells can contribute to allergic airway inflammation and that targeting these pathways may be of benefit in human airway inflammation.
Keywords: airway epithelium; apoptotic cells; phagocytosis; IL-10; IL-33
The epithelial cells of the airways serve not only as a barrier to pathogens and allergens they also regulate immune responses and play a crucial role in the pathogenesis of allergic asthma. When exposed to allergens, bronchial epithelial cells produce the inflammatory cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, which contribute to the innate inflammatory responses (1-3). In addition, allergen exposure can disrupt the integrity of the epithelial barrier by inducing apoptosis of bronchial epithelial cells (4). The maintenance of barrier integrity and function necessitates rapid and efficient clearance of these apoptotic cells as secondary necrosis leads to the release of additional IL-33 (5, 6). Interestingly, clusters of apoptotic bronchial epithelial cells known as "Creola bodies" are regularly seen in the sputum of patients with asthma, suggesting that the phagocytosis and clearance of apoptotic cells in the airways of these individuals is either impaired or insufficient (7-9). Apoptotic cells can be cleared by professional phagocytes, that is, macrophages, neutrophils, and dendritic cells, or by nonprofessional phagocytes, for example, fibroblasts and epithelial cells. In a publication from our laboratory, we investigated the role of bronchial epithelial cells in apoptotic cell clearance and the effect of...