Fpr2/ALX 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. As anti-inflammatory therapies limit thrombosis and anti-thrombotic therapies reduce vascular inflammation, we tested the therapeutic potential of two pro-resolving endogenous mediators: Annexin A1 N-terminal derived peptide (AnxA1Ac2-26) and aspirin (ASA) triggered lipoxin A4 (ATL, 15-epi-lipoxin A4), on the cerebral microcirculation following ischemia-reperfusion (I/R) injury. Furthermore, we tested whether the lipoxin A4 receptor, formyl-peptide receptor 2/3 (Fpr2/3, ortholog to human FPR2/ALX), evoked neuro-protective functions following cerebral I/R injury.
Methods and Results—Using intravital microscopy, we found that cerebral I/R injury was accompanied by neutrophil and platelet activation and neutrophil-platelet aggregate (NPA) formation within cerebral microvessels. Moreover, ATL activation of neutrophil Fpr2/3 regulated NPA formation in the brain, and inhibited the reactivity of the cerebral microvasculature. The same results were obtained with AnxA1Ac2-26; administration. Blocking Fpr2/ALX with the antagonist Boc2 reversed this effect, and treatments were ineffective in Fpr2/3 knockout mice, who displayed an exacerbated disease severity, evidenced by increased infarct area, blood brain barrier dysfunction, increased neurological score and elevated levels of cytokines. Furthermore, ASA treatment significantly reduced cerebral leukocyte recruitment, and increased endogenous levels of ATL, effects again mediated by Fpr2/3.
Conclusions—In summary, Fpr2/ALX is a therapeutic target for initiating endogenous pro-resolving, anti-inflammatory pathways following cerebral I/R injury.
- Received November 29, 2015.
- Revision received March 9, 2016.
- Accepted April 4, 2016.