Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice.
BACKGROUND
Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. High cholesterol has been recognized as a risk factor in asthma; however, the mechanism of this linkage is not known.


METHODS
To explore the importance of cholesterol homeostasis for asthma, we investigated the contribution of LXR activity in an ovalbumin- and a house dust mite-driven eosinophilic asthma mouse model.


RESULTS
In both models, airway inflammation, airway hyper-reactivity, and goblet cell hyperplasia were reduced in mice deficient for both LXRα and LXRβ isoforms (LXRα(-/-)β(-/-)) as compared to wild-type mice. Inversely, treatment with the LXR agonist GW3965 showed increased eosinophilic airway inflammation. LXR activity contributed to airway inflammation through promotion of type 2 cytokine production as LXRα(-/-)β(-/-) mice showed strongly reduced protein levels of IL-5 and IL-13 in the lungs as well as reduced expression of these cytokines by CD4(+) lung cells and lung-draining lymph node cells. In line herewith, LXR activation resulted in increased type 2 cytokine production by the lung-draining lymph node cells.


CONCLUSIONS
In conclusion, our study demonstrates that the cholesterol regulator LXR acts as a positive regulator of eosinophilic asthma in mice, contributing to airway inflammation through regulation of type 2 cytokine production.
Department of Biomedical Molecular Biology Ghent University Ghent Belgium.
Muriel
M
Smet
Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium; Medical Biotechnology CenterFlanders Institute for BiotechnologyGhentBelgium.
Lien
L
Van Hoecke
Department of Biomedical Molecular Biology Ghent University Ghent Belgium.
Ans
A
De Beuckelaer
Department of Biomedical Molecular Biology Ghent University Ghent Belgium.
Seppe
S
Vander Beken
Department of Biomedical Molecular Biology Ghent University Ghent Belgium.
Thomas
T
Naessens
Department of Respiratory MedicineGhent University HospitalGhentBelgium; Inflammation Research CenterFlanders Institute for BiotechnologyGhentBelgium.
Karl
K
Vergote
Department of Respiratory MedicineGhent University HospitalGhentBelgium; Inflammation Research CenterFlanders Institute for BiotechnologyGhentBelgium.
Monique
M
Willart
Department of Respiratory MedicineGhent University HospitalGhentBelgium; Inflammation Research CenterFlanders Institute for BiotechnologyGhentBelgium.
Bart N
BN
Lambrecht
Department of Biosciences and Nutrition at NovumKarolinska InstitutetStockholmSweden; Department of Biology and BiochemistryUniversity of HoustonHoustonTexas.
Jan-Åke
JÅ
Gustafsson
Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden.
Knut R
KR
Steffensen
Department of Biomedical Molecular Biology Ghent University Ghent Belgium.
Johan
J
Grooten
asthma; cholesterol; eosinophilic airway inflammation; liver X receptor