Dual modulation of formyl peptide receptor 2 by aspirin-triggered lipoxin contributes to its anti-inflammatory...

The eicosanoid lipoxin A₄ and aspirin-triggered 15-epi-lipoxin A₄ (ATL) are potent anti-inflammatory agents. How their anti-inflammatory effects are mediated by receptors such as the formyl peptide receptor 2 (FPR2/ALX) remains incompletely understood. In the present study, fluorescent biosensors of FPR2/ALX were prepared and ATL-induced conformational changes were recorded. A biphasic dose curve consisting of a descending phase and an ascending phase was observed, with the descending phase corresponding to diminished FPR2 response such as Ca²⁺ mobilization induced by the potent synthetic agonist WKYMVm. Preincubation of FPR2-expressing cells with 100 pM of ATL also lowered the threshold for WKYMVm to induce β-arrestin-2 membrane translocation, and inhibited WKYMVm-induced interleukin 8 secretion, suggesting signaling bias favoring anti-inflammatory activities. At 100 pM and above, ATL-induced receptor conformational changes resembling that of the WKYMVm along with a weak but measurable inhibition of forskolin-induced cAMP accumulation. However, no Ca²⁺ mobilization was induced by ATL until its concentration reached 1 µM. Taken together, these results suggest a dual regulatory mechanism by which ATL exerts anti-inflammatory effects through FPR2/ALX.