Polymorphonuclear neutrophil infiltration into ischemic infarctions: myth or truth?

Abstract

Knowledge builds on steps considered scientific truths,which shall endure the test of time and variations in cir-cumstances. For decades, neuropathologists have used thesequence of cellular changes including immune cell reac-tion in infarcted brain tissue for timing the development ofthe infarction [1, 13]. A generally accepted concept hasbeen that polymorphonuclear neutrophils (PMN) can causeplugging of microvessels within the vascular territory of anoccluded artery even when reperfused [2], and theyextravasate and invade the brain parenchyma at earlystages of infarction (within 15–24 h; e.g., [1, 10, 11, 13, 15,17]. The infiltration of PMNs into ischemic infarcts has ledto the hypothesis that besides adhering to the endotheliumand plugging microvessels before extravasation (no-reflowphenomenon), PMNs release a palette of neurotoxic sub-stances, which contribute to neuronal cell death as acomponent of ischemia–reperfusion injury. Having beenconfirmed in many experimental brain ischemia studies,this hypothesis has stimulated trials of therapeutic inter-ventions based on combatting this PMN response byvarious means (e.g., [5, 14]). Such therapeutic trials tar-geting PMNs have given inconsistent results in bothexperimental studies and clinical trials.This has prompted Drs. Engelhardt and Sorokin torecruit—as the authors state it—a multicenter team com-prising stroke researchers, neuropathologists and basicscientists for collaborative investigation to determine thetemporo-spatial relationship between immune cells andblood vessel microarchitecture in the mouse and humanbrain at early (acute) stages after ischemia. The authorshave applied a wide arsenal of elaborate methods. Tran-sient focal ischemia was induced in mice by occluding themiddle cerebral artery for 30–90 min with a microfilamentfollowed by recirculation from 6 h up to 2 weeks. Com-parison with human cases was performed by assessingbrain histopathology in 25 human victims of stroke. Inaddition, under in vitro flow conditions, they have testedPMN migration across the endothelial monolayer exposedto oxygen and glucose deprivation.The results of the study of Enzmann et al. [6] arechallenging to neuropathologists, who for decades haveobserved PMN infiltration and interpreted it as an inherentcomponent in the sequence of events in infarct maturation.Using specific markers for inflammatory cells and forstructures of the neurovascular unit, Enzmann et al. putforth that in their experimental ischemia model PMNs