FPR2/ALX is a therapeutic target for the resolution of inflammation.

Abstract

Unregulated inflammation underlies many diseases, including sepsis: a serious clinical problem, causing around 1.8m deaths worldwide each year. Much interest lies in targeting inflammation. One such potential target is the interaction of annexin A1 (AnxA1) with its receptor, FPR2/ALX. We investigated the potential role of this mechanism in a murine model of sepsis-associated cerebral inflammation (i.p. injection of lipopolysaccharide, LPS: 10μg/mouse; n=6 mice/group). Measurements (e.g. cellular interactions quantified by intravital microscopy) were made 2h post toxin injection. LPS induced increased leukocyte rolling and adhesion and vascular wall permeability in cerebral venules together with elevations in brain myeloperoxidase and serum pro-inflammatory cytokines in wild-type mice. These responses were exacerbated in AnxA1-null mice. The AnxA1-mimetic peptide, Ac2-26, mitigated LPS-induced leukocyte adhesion in wild-type and AnxA1-null mice, with Boc2 (pan-FPR antagonist) attenuating the effects. Both the non-selective FPR agonists, fMLP and Ac2-26, and the FPR2 selective agonist ATLa, were without effect in Fpr2-null mice. In conclusion, our novel results demonstrate the importance of the AnxaA1/FPR2 system in effecting the resolution of cerebral inflammation in experimental sepsis and may therefore provide a novel anti-inflammatory therapeutic target for the treatment of sepsis.