Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice.

Muriel Smet,Karl Vergote,Thomas Naessens,Monique Willart,Bart N Lambrecht,Seppe Vander Beken,Lien Van Hoecke,Johan Grooten,Knut R Steffensen,Ans De Beuckelaer,Jan-Åke Gustafsson

doi:10.1002/iid3.118

Abstract

IntroductionLiver 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.MethodsTo 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.ResultsIn 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.ConclusionsIn 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.

Highlights

Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis
We addressed the role of the cholesterol-sensing nuclear receptor LXR in the pathogenesis of eosinophilic allergic asthma
We showed that in this mouse model, a significantly attenuated airway inflammation is seen in mice that are deficient for both the a- and b-isoform of LXR

Summary

Introduction

Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. 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. Asthma is a chronic disease of the airways that presents as recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing These symptoms are associated with airway inflammation, airway remodeling, and airway hyper-reactivity (AHR). Dyslipidemia, characterized by high cholesterol levels in the blood, has gained interest as a risk factor for asthma This is due to the fact that several epidemiological studies have shown a positive association between dyslipidemia and asthma symptom severity both in children and adults [4,5,6,7,8,9,10]. Hypercholesterolemia in mice has been shown to result in more severe allergen-induced eosinophilic airway inflammation as well as in increased AHR and goblet cell hyperplasia [11, 12]

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Results

Conclusion