Resolving Thrombo‐inflammation following ischemia reperfusion injury

Abstract

BackgroundThe intertwined processes of thrombosis and inflammation resulting in inadequate resolution are major pathophysiological contributors of ischemia reperfusion injury (I/RI). Accumulating data supports the hypothesis that anti‐inflammatory therapies may limit thrombosis and that anti‐thrombotic therapies may reduce vascular inflammation. One such target is the anti‐inflammatory and pro‐resolving endogenous mediator Annexin A1 (AnxA1). Whilst much work has focused on the effect of AnxA1 on leukocyte accumulation during I/RI, less is known regarding its effect on platelets. Here we tested for the first time the therapeutic potential AnxA1 in resolving thrombo‐inflammation after I/RI.Material and MethodsWe used a well‐characterized model of transient middle cerebral artery occlusion with reperfusion (MCAo/R), coupled with pharmacological and genetic approaches. Fluorescence intravital microscopy (IVM) was used to monitor thrombo‐inflammatory responses, along with flow cytometry and ELISAs. (All animal experiments were approved by LSUHSC‐S Animal Care and Use Committee and were conducted in accordance with the American Association for Accreditation of Laboratory Animal Care guidelines and complied with ARRIVE [Animal Research: Reporting In Vivo Experiments]).ResultsIVM revealed heightened platelet adherence and aggregate formation within cerebral microvessels post I/RI. Using AnxA1 knock‐out mice, we found heightened cellular (neutrophil and platelet) activation as well as neutrophil‐platelet aggregate formation within the cerebral microcirculation. Administration of AnxA1 reduced platelet adherence to the inflamed cerebral endothelium following I/RI, along with a reduction in thrombus formation, thereby facilitating the resolution of thrombo‐inflammation post cerebral I/RI.ConclusionHerein we found a previously unknown phenomenon that the endogenous anti‐inflammatory and pro‐resolving mediator AnxA1 is able to exert protection through the alteration of platelet responses by orchestrating the delicate platelet phenotype in I/RI from pro‐pathogenic to regulatory. Thus, AnxA1 is a possible therapeutic strategy for effecting the resolution of cerebral thrombo‐inflammation and may therefore provide a novel anti‐thrombo‐inflammatory therapeutic target following ischemic insults.Support or Funding InformationDr. Gavins acknowledges the support of the National Institutes of Health/National Heart, Lung, and blood Institute (NIH/NHLBI): HL125572‐01A1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.