Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans

TL;DR

This study shows that epoxy-oxylipins control monocyte behavior during inflammation in humans, offering a new approach to treat chronic inflammatory diseases.

Contribution

The study identifies a novel mechanism by which epoxy-oxylipins regulate monocyte differentiation and inflammation resolution in humans.

Findings

Epoxy-oxylipins are present in human blood and increase during inflammation.

Inhibiting sEH reduces intermediate monocytes and accelerates pain resolution.

12,13-EpOME blocks monocyte transition via p38 MAPK, confirmed in vivo and in vitro.

Abstract

The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins. GSK2256294, a selective sEH inhibitor specifically elevates 12,13-EpOME and 14,15-EET. While inhibition of sEH hastens pain resolution, it has no effect on tissue heat, redness and swelling. GSK2256294, however, significantly reduces numbers of circulating intermediate monocytes that expand during inflammation. We find that 12,13-EpOME blocks the transition of classical to intermediate monocytes in a p38 MAPK-dependent manner, results that are recapitulated when blocking p38 MAPK in vitro and when administering the p38 MAPK inhibitor losmapimod in vivo to healthy volunteers. Furthermore, fewer intermediate monocytes are observed at the site of inflammation, accompanied by reduced tissue CD4 T cells. Hence, we have mapped the expression, activity and function of epoxy-oxylipins in human inflammation revealing new mechanisms of monocyte differentiation and resolution biology.

Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

Figures