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

doi:10.1152/ajplung.00110.2011

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

12 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume	302
Issue number	2
Pages (from-to)	L206-15
DOIs	https://doi.org/10.1152/ajplung.00110.2011
Publication status	Published - Jan 2012

Keywords

Alleles
Allergens
Amino Acid Substitution
Animals
Antigens, Dermatophagoides
Apolipoproteins E
Asthma
Bronchial Hyperreactivity
Chemokine CCL11
Chemokine CCL24
Chemokine CCL7
Cytokines
Disease Models, Animal
Female
Gene Knock-In Techniques
Genotype
Immunoglobulin E
Inflammation
Lung
Metaplasia
Mice
Mice, Inbred C57BL
Mice, Transgenic
RNA, Messenger
Th17 Cells
Th2 Cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1152/ajplung.00110.2011

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Yao, X., Dai, C., Fredriksson, K., Lam, J., Gao, M., Keeran, K. J., Nugent, G. Z., Qu, X., Yu, Z-X., Jeffries, N., Lin, J., Kaler, M., Shamburek, R., Costello, R., Csako, G., Dahl, M., Nordestgaard, B. G., Remaley, A. T., & Levine, S. J. (2012). Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice. American Journal of Physiology - Lung Cellular and Molecular Physiology, 302(2), L206-15. https://doi.org/10.1152/ajplung.00110.2011

Yao, X, Dai, C, Fredriksson, K, Lam, J, Gao, M, Keeran, KJ, Nugent, GZ, Qu, X, Yu, Z-X, Jeffries, N, Lin, J, Kaler, M, Shamburek, R, Costello, R, Csako, G, Dahl, M, Nordestgaard, BG, Remaley, AT & Levine, SJ 2012, 'Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 302, no. 2, pp. L206-15. https://doi.org/10.1152/ajplung.00110.2011

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title = "Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice",

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.",

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author = "Xianglan Yao and Cuilian Dai and Karin Fredriksson and Jonathan Lam and Meixia Gao and Keeran, {Karen J} and Nugent, {Gayle Zywicke} and Xuan Qu and Zu-Xi Yu and Neal Jeffries and JingPing Lin and Maryann Kaler and Robert Shamburek and Rene Costello and Gyorgy Csako and Morten Dahl and Nordestgaard, {B{\o}rge G} and Remaley, {Alan T} and Levine, {Stewart J}",

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language = "English",

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T1 - Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

AU - Yao, Xianglan

AU - Dai, Cuilian

AU - Fredriksson, Karin

AU - Lam, Jonathan

AU - Gao, Meixia

AU - Keeran, Karen J

AU - Nugent, Gayle Zywicke

AU - Qu, Xuan

AU - Yu, Zu-Xi

AU - Jeffries, Neal

AU - Lin, JingPing

AU - Kaler, Maryann

AU - Shamburek, Robert

AU - Costello, Rene

AU - Csako, Gyorgy

AU - Dahl, Morten

AU - Nordestgaard, Børge G

AU - Remaley, Alan T

AU - Levine, Stewart J

PY - 2012/1

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N2 - 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.

AB - 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.

KW - Alleles

KW - Allergens

KW - Amino Acid Substitution

KW - Animals

KW - Antigens, Dermatophagoides

KW - Apolipoproteins E

KW - Asthma

KW - Bronchial Hyperreactivity

KW - Chemokine CCL11

KW - Chemokine CCL24

KW - Chemokine CCL7

KW - Cytokines

KW - Disease Models, Animal

KW - Female

KW - Gene Knock-In Techniques

KW - Genotype

KW - Immunoglobulin E

KW - Inflammation

KW - Lung

KW - Metaplasia

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - RNA, Messenger

KW - Th17 Cells

KW - Th2 Cells

U2 - 10.1152/ajplung.00110.2011

DO - 10.1152/ajplung.00110.2011

M3 - Journal article

C2 - 22058162

SN - 1040-0605

VL - 302

SP - L206-15

JO - American Journal of Physiology: Lung Cellular and Molecular Physiology

JF - American Journal of Physiology: Lung Cellular and Molecular Physiology

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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