Interleukin-6 mediates enhanced thrombus development in cerebral arterioles following a brief period of focal brain ischemia

The cerebral microvasculature is rendered more vulnerable to thrombus formation following a brief (5.0min) period of focal ischemia. This study examined the contribution of interleukin-6 (IL-6), a neuroprotective and prothrombotic cytokine produced by the brain, to transient ischemia-induced thrombosis in cerebral arterioles. The middle cerebral artery of C57BL/6J mice was occluded for 5min, followed by 24h of reperfusion (MCAo/R). Intravital fluorescence microscopy was used to monitor thrombus development in cerebral arterioles induced by light/dye photoactivation. Thrombosis was quantified as the time of onset of platelet aggregation on the vessel wall and the time for complete blood flow cessation. MCAo/R in wild type (WT) mice yielded an acceleration of thrombus formation that was accompanied by increased IL-6 levels in plasma and in post-ischemic brain tissue. The exaggerated thrombosis response to MCAo/R was blunted in WT mice receiving an IL-6 receptor-blocking antibody and in IL-6 deficient (IL-6−/−) mice. Bone marrow chimeras, produced by transplanting IL-6−/− marrow into WT recipients, did not exhibit protection against MCAo/R-induced thrombosis. The increased vulnerability of the cerebral vasculature to thrombus development after MCAo/R is mediated by IL-6, which is likely derived from brain cells rather than circulating blood cells. These findings suggest that anti-IL-6 therapy may reduce the likelihood of cerebral thrombus development after a transient ischemic attack. •Transient brain ischemia accelerated thrombus formation in cerebral arterioles.•The enhanced thrombosis response was associated with elevated brain & plasma IL-6.•Genetic or immunologic blockade of IL-6 blunted the ischemia-enhanced thrombosis.•The IL-6 mediating this response is derived from brain cells rather than blood cells.