Temporal and Spatial Dynamics of Inflammasome Activation After Ischemic Stroke

Abstract

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive. Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated. Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1β, IL-18, and GSDMD, peaked at 3–5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and −11 served as the main executing enzymes. Inhibiting Caspase-1/−11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P < 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P < 0.001). Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.