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.
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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)
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Chemical References |
- Allergens
- Dust
- Il33 protein, mouse
- Interleukin-33
- Interleukins
- Interleukin-10
- Ovalbumin
- rac1 GTP-Binding Protein
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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)
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