Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke

Ischemia/reperfusion (I/R) injury following stroke can worsen patient outcome through excess inflammation. This study investigated the pharmacologic potential of targeting an endogenous anti-inflammatory circuit via formyl peptide receptor (FPR) 2/lipoxin receptor (ALX) (Fpr2/3 in mouse) in global cerebral I/R. Mice (C57BL/6 and Fpr2/3(-/-)) were subjected to bilateral common carotid artery occlusion, followed by reperfusion and treatment with FPR agonists: AnxA1(Ac2-26) [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 mu/kg] and 15-epimer-lipoxin A4 (15-epi-LXA(4); FPR2/ALX specific, 12.5 and 100 ng/kg). Leukocyte-endothelial (L-E) interactions in the cerebral microvasculature were then quantified in vivo using intravital fluorescence microscopy. 15-epi-LXA(4) administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA(4)) to levels seen in sham-operated animals. AnxA1(Ac2-26) treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1(Ac2-26) plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 mu/kg) abrogated the effects of AnxA1(Ac2-26) fully at 40 min. Antagonists were less effective at 2 h, which we demonstrate is likely because of their impact on early L-E interactions. Our findings indicate that FPR2/ALX activity elicits considerable control over vascular inflammatory responses during cerebral I/R and, therefore, provide evidence that targeting FPR2/ALX may be beneficial for patients who suffered from stroke.Higher Education Funding Council for EnglandLouisiana State Univ, Hlth Sci Ctr, Mol & Cellular Physiol Dept, Shreveport, LA 71105 USAUniv London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, London W12 0NN, EnglandUniversidade Federal de São Paulo, Dept Morphol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol, São Paulo, BrazilWeb of Scienc