Blocking of platelet glycoprotein receptor Ib reduces “thrombo-inflammation” in mice with acute ischemic stroke

Abstract

BackgroundIschemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation.MethodsFocal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO.ResultsBlocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls.ConclusionIn acute ischemic stroke, thrombus formation and inflammation are closely intertwined (“thrombo-inflammation”). Blocking of platelet GPIb can ameliorate thrombo-inflammation.

von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke

“…By specifically blocking the VWF-GPIbα axis, anfibatide reduced the number of fibrin(ogen)-positive blood vessels and microthrombi in the ischemic hemisphere (49,51). In line with these results, anti-GPIbα treatment significantly reduced thrombus burden in the cerebral microvasculature, as measured by the number of GPIX-positive platelet aggregates and occluded brain vessels (61). Correspondingly, ADAMTS13 deficient mice showed an increased number of thrombi containing fibrin and VWF in the brain lesions after stroke (53).…”

“…Interestingly, the increased brain damage and worsened neurological outcome observed in ADAMTS13-deficient animals were abrogated when neutrophils were depleted, indicating a causal role of neutrophils in the exacerbation of ischemic brain injury in the absence of ADAMTS13 (55). Blockade of GPIbα similarly led to decreased expression of IL-6, IL-1ß, and tumor necrosis factor-α (50,61) and was also shown to lower the numbers of infiltrating T-cells and myeloid leukocytes (51,61). The latter is in accordance with recent data from our group showing that inhibition of the VWF-GPIbα interaction results in significantly decreased recruitment of monocytes, neutrophils, and T-cells in the ischemic brain (63).…”

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation

“…2,3 Recent studies have suggested that thrombosis and inflammation are two closely intertwined processes that crucially contribute to ischemic brain injury and orchestrate stroke progression. 4–7 These findings have given rise to the novel concept of “thrombo-inflammation” in which ischemic stroke is considered to be a thrombo-inflammatory disease. 8,9 Accordingly, it has been recently proposed that simultaneous targeting of both thrombotic and inflammatory processes could represent a novel therapeutic strategy for acute ischemic stroke.…”

Comparison of the central human and mouse platelet signaling cascade by systems biological analysis

“…platelet aggregation [10][11][12]. Thereby, data sets of several knock-out and knock-in mouse models [13][14][15] have been useful to validate data. Differences between mouse and human signaling cascades have been observed in several cell types including platelets [16][17][18].…”