Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-\u03baB

Lipsa Panda,B S Jayaraj,Atish Gheware,Rakhshinda Rehman,Subbarao V Madhunapantula,Manish K Yadav,Balaram Ghosh,Ulaganathan Mabalirajan,Padukudru Anand Mahesh,Anurag Agrawal

doi:10.1038/s41598-017-09869-9

Abstract

Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15–lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.

Highlights

Linoleic acid, a dietary polyunsaturated fatty acid (PUFA), and its lipid metabolites are known to mediate several inflammatory pathways in asthma
As compared to SHAM, OVA induced mice showed increased infiltration of inflammatory cells and goblet cell metaplasia (GCM), which were alleviated with DEX treatment
For the first time, show that 13-S-hydroxyoctadecadienoic acid (HODE), the 12/15 LOX metabolite of linoleic acid, leads to steroid resistance. This was shown in mice with airway inflammation (AAI) and in cultured human bronchial epithelial cells

Summary

Introduction

A dietary polyunsaturated fatty acid (PUFA), and its lipid metabolites are known to mediate several inflammatory pathways in asthma. There are very limited studies with endogenous factors, present upstream of the phenotype observed in steroid resistance In this context, studying the role of endogenous factors (e.g, lipid metabolites) present in asthmatics may provide better insights into the molecular mechanisms underlying steroid resistance in humans and would be more clinically relevant. Linoleic acid (ω-6 fatty acid), is known to increase the levels of cytokines which leads to neutrophilia[18]. These are known to negatively modulate the binding of synthetic glucocorticoids with glucocorticoid-receptor[19, 20]. Role of dietary lipids and its metabolites is not known in steroid resistance. We further provide evidence to support the role of NF-κB and GR-α in the HODE induced steroid insensitivity

Methods

Results

Conclusion