Formyl-Peptide Receptor 2/3/Lipoxin A4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation Impact for Therapy in Cardiovascular Disease

Background-Platelet activation at sites of vascular injury is essential for hemostasis, but it is also a major pathomechanism underlying ischemic injury. Because anti-inflammatory therapies limit thrombosis and antithrombotic therapies reduce vascular inflammation, we tested the therapeutic potential of 2 proresolving endogenous mediators, annexin A1 N-terminal derived peptide (AnxA1(Ac2-26)) and aspirin-triggered lipoxin A(4) (15-epi-lipoxin A(4)), on the cerebral microcirculation after ischemia/reperfusion injury. Furthermore, we tested whether the lipoxin A(4) receptor formyl-peptide receptor 2/3 (Fpr2/3; ortholog to human FPR2/lipoxin A(4) receptor) evoked neuroprotective functions after cerebral ischemia/reperfusion injury. Methods and Results-Using intravital microscopy, we found that cerebral ischemia/reperfusion injury was accompanied by neutrophil and platelet activation and neutrophil-platelet aggregate formation within cerebral microvessels. Moreover, aspirin-triggered lipoxin A(4) activation of neutrophil Fpr2/3 regulated neutrophil-platelet aggregate formation in the brain and inhibited the reactivity of the cerebral microvasculature. The same results were obtained with AnxA1(Ac2-26) administration. Blocking Fpr2/lipoxin A(4) receptor with the antagonist Boc2 reversed this effect, and treatments were ineffective in Fpr2/3 knockout mice, which displayed an exacerbated disease severity, evidenced by increased infarct area, blood-brain barrier dysfunction, increased neurological score, and elevated levels of cytokines. Furthermore, aspirin treatment significantly reduced cerebral leukocyte recruitment and increased endogenous levels of aspirin-triggered lipoxin A(4), effects again mediated by Fpr2/3. Conclusion-Fpr2/lipoxin A(4) receptor is a therapeutic target for initiating endogenous proresolving, anti-inflammatory pathways after cerebral ischemia/reperfusion injury.