PURPOSE OF THE STUDY.
Airway epithelial cells naturally undergo programmed cell death, or apoptosis, after encounter with airborne allergens and pollutants. The authors investigated how these apoptotic cells are cleared by the lungs, and whether this process was important in preventing airway inflammation.
Studies were performed in mice and by using human cells.
Flow cytometric and histologic assays were used to examine the phagocytic capacity of airway epithelial cells in vitro. For in vivo studies, the authors used genetically modified mice in which proteins were deleted from airway epithelial cells only.
The authors found that airway epithelial cells from humans and mice were able to engulf apoptotic cells, resulting in the secretion of antiinflammatory cytokines, such as interleukin (IL)-10. Uptake of apoptotic cells was dependent on the intracellular protein Rac1, a GTPase important for cytoskeletal rearrangement during phagocytosis. Mice that lacked Rac1 expression specifically in airway epithelial cells were unable to effectively clear apoptotic cells from the lungs. This defect in phagocytosis resulted in decreased secretion of antiinflammatory cytokines, exaggerated airway inflammation after challenge with house dust mite allergens, and failure to develop tolerance to inhaled antigens. The inflammatory cytokine IL-33 was elevated in Rac1-deficient lungs, which was associated with expansion of proallergic innate lymphoid cells. Furthermore, suppression of Rac1 in human nasal epithelial cells resulted in enhanced production of IL-33, suggesting that Rac1 negatively regulates inflammatory signaling pathways. Finally, treatment with IL-10 was shown to mitigate the allergic inflammation seen in Rac1-deficient airways.
Clearance of apoptotic cells by airway epithelial cells is important for preventing allergen-induced airway inflammation.
It is generally thought that traditional phagocytic cells in the lungs, such alveolar macrophages, are primarily responsible for keeping the airways clean through removal of cellular debris and inhaled particulates. However, this study reveals that airway epithelial cells, which are not typically known for their phagocytic function, play a critical role in the clearance of apoptotic cells and in maintaining an antiinflammatory environment in the lungs. This study, along with others evaluating innate immune activity of epithelial cells, emphasizes the importance of the respiratory mucosal barrier in maintaining lung homeostasis. Therapies aimed at enhancing the immunosuppressive activity of airway epithelial cells, or blocking their release of proinflammatory cytokines such as IL-33, may prove beneficial for the treatment of asthma and other immune-mediated respiratory diseases.
- Copyright © 2013 by the American Academy of Pediatrics