Abstract WMP80: Inflammation in Aging Increases Ischemic Stroke Burden

Abstract

Rationale: Acute increases the risk for stroke and adverse outcomes following stroke, such as disability and death. Aging is characterized by increased circulating inflammatory agonists, including interferons (IFNs), and hyperactive platelets. However, whether IFNs generated during aging enhance platelet activation to promote ischemic stroke remains uncertain. Objective: We determined whether IFNs regulate platelet activation and ischemic stroke during human and murine aging. Methods: Younger (8-12 weeks) or aged (>18 months) male mice were stimulated in vivo with IFNα or vehicle control (t=4 days). Mice were then subject to the transient middle cerebral artery occlusion stroke model (t=1 hour followed by reperfusion for 24 hours). Mortality and stroke infarct size were determined. In parallel, we assessed the expression of interferon-sensitive genes (ISGs) and platelet activation from IFN or control treated mice. We also examined platelet activation and ISGs in platelets from younger (age<45) and older (age>65) adults. Results: In aged mice, IFNα significantly increased infarct size (56.2±5.5mm 3 vs 27.3 ±3.0 mm 3 , p<0.0001) and mortality (55% vs. 10%, p<0.05) compared to control mice. Consistent with a greater stroke burden, IFNα significantly worsened neurological outcomes. Ex vivo, IFNα significantly increased fibrinogen uptake and platelet aggregation. In comparison, IFNα did not alter infarct size or mortality in younger mice. We next dissected the mechanism controlling IFNα-induced platelet aggregation and stroke. We identified that interferon-induced transmembrane proteins (IFITMs, a type of ISGs) were upregulated in platelets from aged mice and older humans (settings where IFNs and platelet activation are increased). IFITMs also increased significantly in platelets following IFNα simulation in vivo . Deletion of IFITMs was sufficient to rescue IFNα-induced platelet aggregation and thrombosis-related mortality. Conclusion: In aging, IFNα increases platelet aggregation, stroke burden, stroke-related mortality, and neurological deficits. This pathway critically involves platelet IFITMs, which are upregulated in aging and functionally control fibrinogen uptake, platelet aggregation, and thrombosis.