The study shows that the antimicrobial peptide LL‑37 and the inflammatory molecule leukotriene B4 (LTB4) boost each other in immune cells, creating a self‑amplifying inflammation loop. This loop can be dampened by natural anti‑inflammatory lipids like lipoxin A4 and resolvin E1, which act on the same receptors to stop the feedback. For biohackers, it means that boosting resolvin‑producing omega‑3s or using lipoxin‑like compounds might help control excessive inflammation linked to LL‑37 and LTB4.

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, proresolving 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 proinflammatory circuit might be inhibited by LXA(4) and RvE(1) acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.