Human and murine eosinophils differ in their ability to synthesize key bioactive lipids involved in asthma

Abstract

Abstract CONTEXT High eosinophil (EOS) counts is a key feature of asthma. EOS notably affect the asthmatic response by the mean of their lipidome. Mouse models have been developed in the hope of defining new pharmacological targets to treat asthma. However, many pinpointed targets could not be translated into clinics, underscoring that key differences exist between mice and humans. Herein, we compared the ability of human (h) and mouse (m) EOS to synthesize key bioactive lipids from arachidonic acid (AA) and docosahexaenoic acid (DHA). RESULTS In response to AA, hEOS synthesized both LTC4 and LTB4 while mEOS only synthesized LTB4. The synthesis of the 15-lipoxygenase products 15-HETE and 12-HETE also differed, hEOS producing them at a 5:1 ratio while mEOS producing them at a 1:2 ratio. mEOS consistently synthetized more PGE2 than hEOS. As for DHA, mEOS produced ten times the levels of specialized pro-resolving mediators (resolvins, maresins and protectins) than hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-AG and its congener 2-DHG, a biosynthetic pathway that was 10 – 50 times less important in mEOS. CONCLUSIONS Our data show that the lipidomes of hEOS and mEOS differ, notably by their production of leukotrienes, their opposite 15-HETE/12-HETE ratio, their ability to synthesize specialized pro-resolving mediators (mEOS > hEOS), and the inability of mEOS to synthesize anti-inflammatory endocannabinoids. We thus propose that in mouse models of asthma, the impact of LTB4 is likely overrated, the role of specialized pro-resolving mediators amplified, and the role of endocannabinoids underrated, compared to asthmatics.