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Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2012 Jan 15; Vol. 302 (2), pp. L206-15. Date of Electronic Publication: 2011 Nov 04. - Publication Year :
- 2012
-
Abstract
- Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (ε2, ε3, and ε4) reflecting single amino acid substitutions at amino acids 112 and 158. The objective of this study was to assess whether the human apoE alleles modify airway responses to repeated nasal HDM challenges. Mice expressing the human apoE ε2 (huApoE2), ε3 (huApoE3), or ε4 (huApoE4) alleles received nasal HDM challenges, and airway responses were compared with mice expressing the endogenous murine apoE gene (muApoE). huApoE3 mice displayed significant reductions in AHR, mucous cell metaplasia, and airway inflammation compared with muApoE mice. The attenuated severity of airway inflammation in huApoE3 mice was associated with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM-induced airway responses were not modified in mice expressing the huApoE2 allele. We conclude that the polymorphic huApoE alleles differentially modulate HDM-induced airway disease, which can be stratified, in rank order of increasing disease severity, ε3 < ε4 < ε2. These results raise the possibility that the polymorphic apoE alleles may modify disease severity in human asthma.
- Subjects :
- Alleles
Amino Acid Substitution
Animals
Apolipoproteins E metabolism
Asthma immunology
Asthma pathology
Bronchial Hyperreactivity immunology
Bronchial Hyperreactivity pathology
Chemokine CCL11 biosynthesis
Chemokine CCL24 biosynthesis
Chemokine CCL7 biosynthesis
Cytokines biosynthesis
Disease Models, Animal
Female
Gene Knock-In Techniques
Genotype
Immunoglobulin E biosynthesis
Inflammation genetics
Inflammation immunology
Lung immunology
Lung pathology
Metaplasia
Mice
Mice, Inbred C57BL
Mice, Transgenic
RNA, Messenger genetics
RNA, Messenger metabolism
Th17 Cells immunology
Th2 Cells immunology
Allergens immunology
Antigens, Dermatophagoides immunology
Apolipoproteins E genetics
Asthma genetics
Bronchial Hyperreactivity genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1504
- Volume :
- 302
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 22058162
- Full Text :
- https://doi.org/10.1152/ajplung.00110.2011