Stroke‐associated inflammation: is von Willebrand factor a ‘bad guy’?

Ischemic stroke is among the leading causes of mortality and disability in the Western world. Brain vessel occlusion by thrombus or embolus is a primary event triggering tissue injury. Restoration of vessel patency (reperfusion), resulting from thrombolytic therapy, may cause additional damage [1]. Inflammation accompanies stroke in patients and animal models of cerebral ischemia/reperfusion (I/R) [2]. Neutrophils and pro-inflammatory cytokines are central mediators of postischemic inflammation. Neutrophils accumulate in the brain tissue after stroke [3] and peripheral neutrophil count has recently been shown to correlate with incidence of stroke [4]. Neutropenia decreases infarct volume and other signs of cerebral injury in animal models of brain ischemia [5,6]. Therefore, prevention of cerebral inflammation may be beneficial in the treatment of stroke. Basically, three processes can be targeted to suppress deleterious effects of inflammation in the post-ischemic brain: neutrophil recruitment, release of damaging substances and activity of these substances. Mechanisms of neutrophil recruitment by the vessel wall during stroke remain incompletely understood. Brain ischemia induces expression of ICAM-1 [7] and pharmacological inhibition or genetic ablation of ICAM-1 on the endothelium or beta-2 integrins on neutrophils has been reported to protect animals from cerebral injury [8–10]. However, antagonists of the beta-2 integrin MAC-1, CD18 (a beta subunit of beta-2 integrins) or ICAM-1 failed to improve recovery after ischemic stroke in humans [11–13]. Therefore, alternative mechanisms of neutrophil adhesion and extravasation are likely to be involved in the brain after I/R. In the present issue, Khan et al. [14] demonstrate a novel mechanism of neutrophil recruitment to the ischemic brain through von Willebrand factor (VWF) expressed on the endothelial cells. The impact of VWF was more pronounced in the absence of its cleaving enzyme, ADAMTS13, whose protective role in murine ischemic stroke has recently been demonstrated [15,16]. These observations suggest a role for ultra-large multimersofVWFthatmayrecruitneutrophilsdirectlyorinaplateletdependent fashion. A finding that platelet accrual in the postischemic brain vasculature is secondary to neutrophil accumulation suggests a platelet-independent mechanism [17]. Nevertheless, platelets mediate leukocyte rolling inmesenteric venules of ADAMTS13mice [18], whichmakes a platelet-dependent mechanismof neutrophil recruitment also possible. In the transient middle cerebral artery occlusion (MCAO) model used in the study by Khan et al., brain ischemia is followed by a reperfusion stage, during which new portions of ADAMTS13 are constantly delivered to the injured part of the brain. It is known, however, that many patients experience a long period of ischemia and arrive at a hospital after the optimal time window for thrombolytic therapy. During this period, ADAMTS13 supply to the occluded vessel is low and local conditions may well mimic ADAMTS13 deficiency. The occurrence of reperfusion is critical for neutrophil recruitment, for example, mediated by CD18 [9]. Further studies are needed to clarify whether VWF is implicated in neutrophil accumulation and extravasation in non-reperfused stroke. VWF is stored in and secreted from Weibel-Palade bodies (WPBs) in endothelial cells [19]. The findings of Khan and coauthors suggest that inhibition of WPB release could suppress cerebral inflammation and consequently be protective against ischemic injury. Nitric oxide (NO) inhibits WPB secretion via S-nitrosylation of N-ethylmaleimide-sensitive factor [20]. Therefore, one can expect that potentiating local NO production or bringing external NO to the ischemic site could protect brain tissue during I/R. Indeed, mice deficient in endothelial NO synthase were shown to have larger infarct size, whereas administration of NO donors or L-arginine decreased infarct size after MCAO [21,22]. Targeting NO-related pathways is a promising approach to stroke treatment [23] and inhibition of VWF-mediated cerebral inflammation could be a potential mechanism of the beneficial effect of NO. Correspondence: Alexander Brill, Immune Disease Institute, 3 Blackfan Circle, 3rd floor, Boston, MA 02115, USA. Tel. : +1 617 713 8311; fax: +1 617 7138333. E-mail: brill@idi.harvard. edu Journal of Thrombosis and Haemostasis, 10: 1662–1664 DOI: 10.1111/j.1538-7836.2012. 04820.x