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: AnxA1Ac2-26 [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 μg/kg] and 15-epimer-lipoxin A4 (15-epi-LXA4; 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-LXA4 administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA4) to levels seen in sham-operated animals. AnxA1Ac2-26 treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1Ac2-26 plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 μg/kg) abrogated the effects of AnxA1Ac2-26 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. © FASEB.

Citation

Helen K Smith, Cristiane Damas Gil, Sonia M Oliani, Felicity N E Gavins. Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015 May;29(5):2161-71

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PMID: 25690650

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