Neutrophil extracellular traps regulate ischemic stroke brain injury
Frederik Denorme, … , Christian C. Yost, Robert A. Campbell
Frederik Denorme, … , Christian C. Yost, Robert A. Campbell
Published March 31, 2022
Citation Information: J Clin Invest. 2022;132(10):e154225. https://doi.org/10.1172/JCI154225.
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Research Article Hematology

Neutrophil extracellular traps regulate ischemic stroke brain injury

Abstract

Ischemic stroke prompts a strong inflammatory response, which is associated with exacerbated outcomes. In this study, we investigated mechanistic regulators of neutrophil extracellular trap (NET) formation in stroke and whether they contribute to stroke outcomes. NET-forming neutrophils were found throughout brain tissue of ischemic stroke patients, and elevated plasma NET biomarkers correlated with worse stroke outcomes. Additionally, we observed increased plasma and platelet surface–expressed high-mobility group box 1 (HMGB1) in stroke patients. Mechanistically, platelets were identified as the critical source of HMGB1 that caused NETs in the acute phase of stroke. Depletion of platelets or platelet-specific knockout of HMGB1 significantly reduced plasma HMGB1 and NET levels after stroke, and greatly improved stroke outcomes. We subsequently investigated the therapeutic potential of neonatal NET-inhibitory factor (nNIF) in stroke. Mice treated with nNIF had smaller brain infarcts, improved long-term neurological and motor function, and enhanced survival after stroke. nNIF specifically blocked NET formation without affecting neutrophil recruitment after stroke. Importantly, nNIF also improved stroke outcomes in diabetic and aged mice and was still effective when given 1 hour after stroke onset. These results support a pathological role for NETs in ischemic stroke and warrant further investigation of nNIF for stroke therapy.

Authors

Frederik Denorme, Irina Portier, John L. Rustad, Mark J. Cody, Claudia V. de Araujo, Chieko Hoki, Matthew D. Alexander, Ramesh Grandhi, Mitchell R. Dyer, Matthew D. Neal, Jennifer J. Majersik, Christian C. Yost, Robert A. Campbell

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Figure 11

Prophylactic and therapeutic nNIF improves long-term stroke outcomes.

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Prophylactic and therapeutic nNIF improves long-term stroke outcomes. Mi...
Mice were subjected to 45 minutes of tMCAO, after which reperfusion was allowed for 21 days. (A) Mice were treated with SCR (10 mg/kg; n = 14) or nNIF either 1 hour before (prophylactic; 10 mg/kg; n = 13) or 1 hour after stroke onset (therapeutic; 10 mg/kg; n = 11). (B) Weight was measured every day the first week and then every week. (C) Survival was monitored daily for 21 days. (D) Modified neurological severity scoring (mNSS) was performed every week after stroke for 3 weeks. (E) Motor function was assessed on the accelerated rotarod, and latency to fall was recorded every week after stroke for 3 weeks. Groups were compared by 2-way ANOVA (B), log-rank test (C), or Kruskal-Wallis test (D and E). *P < 0.05, **P < 0.01, ***P < 0.001.