Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke.

Abstract

Inflammation contributes significantly to neuronal damage in ischemic stroke, with IL (interleukin)-1 being a key mediator. IL-1Ra (IL-1 receptor antagonist) inhibits IL-1 signaling, successfully reducing inflammation in preclinical and clinical stroke studies. However, in the latest phase II trial of IL-1Ra in ischemic stroke (SCIL-STROKE [Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke]), a secondary mediation analysis uncovered an alternative pathway leading to no overall functional benefit. This was the first IL-1Ra trial where participants (73%) received preceding tPA (tissue-type plasminogen activator), raising the possibility that IL-1Ra and tPA interact negatively in ischemic stroke. We aim to explore this postulated negative interaction. A retrospective analysis of SCIL-STROKE trial data was performed. Next, we used a thromboembolic model of stroke in male wild-type mice (25-35 g; n=10-13), treated with tPA (10 mg/kg, 20-60 minutes poststroke), followed by IL-1Ra (100 mg/kg) either 6 doses, twice daily (after tPA), or 2 doses at 30 minutes (during tPA) and 3 hours poststroke. The primary outcome was lesion volume at 72 hours, measured by T2-magnetic resonance imaging. Reanalysis of SCIL-STROKE data revealed a 35.8% reduction in plasma IL-1Ra in patients cotreated with preceding tPA, suggesting IL-1Ra degradation. Biochemical assays confirmed IL-1Ra cleavage by plasmin. While replicating the SCIL-STROKE dosing regimen preclinically, no negative interactions were noted. However, when IL-1Ra was administered during thrombolysis, it impaired the beneficial effect of tPA, reducing lesion volume by only 15%, compared with 68% with tPA alone. Acute cotreatment of IL-1Ra and tPA also led to reduced tissue perfusion and increased leukocyte infiltration and neutrophil extracellular traps. We show that IL-1Ra is cleaved by plasmin, and its administration during thrombolysis worsens outcomes poststroke. These studies confirm a negative interaction between the 2 drugs, which can be prevented by tPA preceding IL-1Ra treatment. The findings raise broader concerns about how tPA may interfere with other neuroprotective treatments.