A novel approach to treatment of thromboembolic stroke in mice: Redirecting neutrophils toward a peripherally implanted CXCL1-soaked sponge

Abstract

Neutrophils are considered key participants in post-ischemic stroke inflammation. They are the first white blood cells to arrive in ischemic brain and their presence in the brain tissue positively correlates with post-ischemic injury severity. CXCL1 is a neutrophil attractant chemokine and the present study evaluates whether redirecting neutrophil migration using a peripherally implanted CXCL1-soaked sponge can reduce brain inflammation and improve outcomes in a novel mouse model of thromboembolic (TE) stroke. TE stroke was induced by injection of a platelet-rich microemboli suspension into the internal carotid artery of adult C57BL/6 male mice. The model induced neuroinflammation that was associated with increases in multiple brain and serum cytokines/chemokines at the mRNA and protein levels, including very marked increases in CXCL1. In other groups of animals, an absorbable sterile hemostatic sponge, previously immersed in either saline (0.9%NaCl) or CXCL1, was implanted into subcutaneous pockets formed in the inguinal region on the left and right side following stroke surgery. Mice implanted with the sponge soaked with CXCL1 had significantly reduced neuroinflammation and infarct size after TE stroke compared to mice implanted with the sponge soaked with 0.9%NaCl. There was also reduced mortality and improved neurological deficits in the TE stroke + CXCL1 sponge group compared to the TE stroke +0.9%NaCl sponge group. In conclusion: redirecting bloodstream leukocytes toward a peripherally-implanted neutrophil chemokine CXCL1-soaked sponge improves outcomes in a novel mouse model of thromboembolic stroke. The present findings suggest a novel therapeutic strategy for patients with acute stroke.