Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation.

Abstract

Lung epithelial cells can influence immune responses to airway allergens. Airway epithelial cells also undergo apoptosis after encountering environmental allergens; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells. Administration of exogenous IL-10 'rescued' the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.

• Authors: Ignacio J Juncadella, Alexandra Kadl, Ashish K Sharma, Yun M Shim, Amelia Hochreiter-Hufford, Larry Borish, Kodi S Ravichandran
• Journal: Nature (Nature) Vol. 493 Issue 7433 Pg. 547-51 (Jan 24 2013) ISSN: 1476-4687 [Electronic] England
• PMID: 23235830 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Dust
• Il33 protein, mouse
• Interleukin-33
• Interleukins
• Interleukin-10
• Ovalbumin
• rac1 GTP-Binding Protein

Topics

• Allergens (immunology)
• Animals
• Apoptosis
• Bronchi (cytology, immunology, pathology)
• Bronchoalveolar Lavage Fluid (chemistry, immunology)
• Dust (immunology)
• Epithelial Cells (immunology, physiology)
• Immunity, Innate (immunology)
• Inflammation (immunology, pathology)
• Interleukin-10 (biosynthesis, immunology)
• Interleukin-33
• Interleukins (biosynthesis, immunology)
• Lung (immunology, pathology)
• Mice
• Ovalbumin (immunology)
• Phagocytosis
• Pyroglyphidae (immunology)
• Respiratory Hypersensitivity (immunology, pathology)
• Th2 Cells (immunology, metabolism)
• Up-Regulation
• rac1 GTP-Binding Protein (deficiency, genetics, metabolism)