Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners.

Anne-Sophie Archambault,Louis-Philippe Boulet,Cyril Martin,Michel Laviolette,Émilie Bernatchez,Julyanne Brassard,Nicolas Flamand,Marie-Renée Blanchet,Vincenzo Di Marzo

doi:10.3390/cells11010141

Abstract

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

Highlights

Asthma is a chronic respiratory disease characterized by airway remodeling, hyperresponsiveness and inflammation [1,2]
The first step to ensure an adequate comparison between hEOS and marrow-derived eosinophils (mEOS) was to secure the access of mEOS given that it was not possible to isolate them from blood due to their low number
Manythat mouse models of asthma developed over the years identify targets could limit this asthma were developed over the years to identify molecular targets that could limit this infiltration

Summary

Introduction

Asthma is a chronic respiratory disease characterized by airway remodeling, hyperresponsiveness and inflammation [1,2]. The development of mouse models was helpful to understand the pathogenesis of eosinophilic asthma and to study the role of eosinophils. These models helped to pinpoint pharmacological targets to treat asthma, such as IL-5 or cysteinyl-leukotrienes (cysLTs) [4]. Many pinpointed targets did not translate into clinical benefits, underscoring that key differences exist between mice and humans. The inhibition of leukotriene (LT) B4 biosynthesis/effects in mice blocked the development/severity of the asthmatic response [5,6]. Key differences in the migration of EOS between humans (h) and mice (m) have been documented.

Methods

Results

Conclusion