Abstract
Background: Multiple sensors, executors and products are involved in inflammasome activation. Inflammasome activation has been found in several immune cells after stroke. However, the molecular mechanisms, the temporal and spatial dynamics of inflammasome activation in stroke remain elusive. Therapeutic value of modifying inflammasome activation in stroke is still debatable. Methods: Inflammasome markers of NLRP3 and IL-1β in stroke patients and healthy control were evaluated with flow cytometry. Correlation of NLRP3/IL-1β expression with stroke outcomes of patients was assessed. Ischemic stroke was induced in mice with transient middle cerebral artery occlusion (tMCAO, 1h). Expression dynamics of inflammasome components, location and cellular target of inflammasome activation in tMCAO models were analyzed. Therapeutic effects of inhibiting inflammasome activation on stroke outcomes were evaluated. Results: Rapid increase of inflammasome markers NLRP3 and IL-1β was detected at 1d after disease onset in stroke patients, which was positively correlated with patients’ infarct volume and NIHSS score. The sensors of NLRP3 and NLRC4 were involved in post stroke inflammasome activation, which increased at 1-3d after stroke and peaked at 3-5d in tMCAO models. Similar dynamics of the executors cleaved Caspase-1/11, as well as the products IL-1β, IL-18 and GSDMD were detected. AIM2 and Caspase-8 seemed not to take any part in post-stroke inflammasome activation. Macrophage was demonstrated as the main cell in which inflammasome was formed in both patients and mice, while microglia, dendritic cells and neutrophil also had inflammasome formation. Inflammasome activation of macrophage was mostly detected in stroke lesion. The executors of Caspase-1 and -11 were the key factors in inflammasome activation in stroke. Preventing inflammasome activation by inhibiting Caspase-1/11 signalings showed promising therapeutic efficacy. Conclusion: The impact of inflammasome activation is detrimental to ischemic stroke. Inhibiting Caspase-1/11 signalings is a promising therapeutic strategy for stroke.
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