Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1

In humans, the antimicrobial peptide LL-37 and leukotriene B-4 (LTB4) are important proinflammatory mediators, whereas lipoxin A(4) (LXA(4)) and resolvin E1 (RvE1) possess anti-inflammatory, proresolving properties. Previously, we reported that LTB4 triggers LL-37 release from human neutrophils (PMNs) and, conversely, that LL-37 promotes LTB4 production from these cells. Here we show that this effect of LL-37 is mediated via the GPCR FPR2/ALX. LL-37 (5-30 mu g/ml) induces intracellular calcium mobilization in a dose-dependent manner, and the signal transduction leading to LTB4 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 LTB4 release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB4-induced LL-37 production from PMNs at 1-100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB4-induced LL-37 release at the same concentrations. Hence, in human neutrophils, binding of LL-37 to FPR2/ALX promotes LTB4 production, which can bind to BLT1 and elicit further LL-37 release. This proinflammatory circuit might be inhibited by LXA(4) and RvE1 acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.-Wan, M., Godson, C., Guiry, P. J., Agerberth, B., Haeggstrom, 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