Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

Xianglan Yao, Cuilian Dai, Karin Fredriksson, Jonathan Lam, Meixia Gao, Karen J. Keeran, Gayle Zywicke Nugent, Xuan Qu, Zu Xi Yu, Neal Jeffries, Jingping Lin, Maryann Kaler, Robert Shamburek, Rene Costello, Gyorgy Csako, Morten Dahl, Børge G. Nordestgaard, Alan T. Remaley, Stewart J. Levine

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    Abstrakt

    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.

    OriginalsprogEngelsk
    Sider (fra-til)206-215
    Antal sider10
    TidsskriftAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
    Vol/bind302
    Udgave nummer2
    DOI
    StatusUdgivet - 1 jan. 2012

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