Leukotriene B 4 /antimicrobial peptide LL‐37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A 4 and resolvin E1

In humans, the antimicrobial peptide LL‐37 and leukotriene B 4 (LTB 4 ) are important proinflammatory mediators, whereas lipoxin A 4 (LXA 4 ) and resolvin E1 (RvE1) possess anti‐inflammatory, prore‐solving properties. Previously, we reported that LTB 4 triggers LL‐37 release from human neutrophils (PMNs) and, conversely, that LL‐37 promotes LTB 4 production from these cells. Here we show that this effect of LL‐37 is mediated via the GPCR FPR2/ALX. LL‐37 (5–30 µg/ml) induces intracellular calcium mobilization in a dose‐dependent manner, and the signal transduction leading to LTB 4 release involves p38 MAP kinase and phosphorylation of cPLA 2 . LXA 4 , an endogenous lipid ligand of FPR2/ALX, and a stable LXA 4 analog [benzo‐LXA 4 ] were ineffective as stimuli at the concentrations of 0.1–10 nM for LTB 4 release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB 4 ‐induced LL‐37 production from PMNs at 1–100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB 4 ‐induced LL‐37 release at the same concentrations. Hence, in human neutrophils, binding of LL‐37 to FPR2/ALX promotes LTB 4 production, which can bind to BLT1 and elicit further LL‐37 release. This proin‐flammatory circuit might be inhibited by LXA 4 and RvE 1 acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.—Wan, M., Godson, C., Guiry, P. J., Agerberth, B., Haeggström, J. Z. Leukotriene B 4 /antimicrobial peptide LL‐37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A 4 and resolvin E1. FASEB J. 25, 1697–1705 (2011). www.fasebj.org