Intracellular signalling mechanisms for neutrophil reactivity in acute ischemic stroke – implications for post-stroke systemic inflammation
NR4A1 is a transcriptional checkpoint that restrains neutrophil activation after cerebral ischemia. In murine models, neutrophil-specific NR4A1 deletion exacerbated infarct size and worsened neurological outcome, whereas pharmacological activation reduced damage and improved recovery in a bicentric preclinical trial. In stroke patients, higher acute NR4A1 expression in neutrophils correlated with favourable three-month outcome, underscoring its translational relevance. Beyond neuroinflammation, neutrophils are the dominant source of circulating cell-free DNA (cfDNA) after stroke, a potent DAMP that amplifies systemic inflammation and vascular comorbidities. NR4A1 suppresses inflammasome activation by binding the NACHT domain of NLRP3, thereby limiting caspase-1 activity, IL-1β release, and downstream proinflammatory gene expression (IL-1α/β, IL-6, Nos2). Loss of NR4A1 amplifies these pathways, reinforcing its role as a broad anti-inflammatory regulator. In the next phase, we define early systemic neutrophil activators post-stroke, dissect how NR4A1 controls inflammasome signalling and NETosis, map neutrophil subpopulations in human stroke, and link NR4A1 expression to patient outcome. These studies aim to establish NR4A1 as a therapeutic target to modulate systemic inflammation and extend treatment opportunities beyond recanalization.
Team
Publications
CD177 Expression on Neutrophils Predicts Ischemic Stroke Outcome in HumansGronewold, J.; Hagemann, N.; Zhang, Y.; Jung, M.; Fleischer, M.; Mohamud Yusuf, A.; Li, A.; Wang, C.; Dzyubenko, E.; Scholtysik, R.; Klein-Hitpass, L.; Kraus, A.; Tuz, A. A.; Singh, V.; Frank, B.; Mönig, A.; Giese, A.; Graser, C.; Niklas, E. M.; Da Silva Rafael, M.; Nanthagopal, M.; Neumann, J.; Kufner, A.; Liman, T. G.; Liu, Y.; Minnerup, J.; Klotz, L.; Giebel, B.; Tertel, T.; Endres, M.; Hermann, D. M.; Gunzer, M.
2026 Stroke
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The Nuclear Receptor NR4A1 Serves as a Neutrophil-Intrinsic Regulator Mitigating Stroke SeverityStrecker, J.-K.; Schmidt, Y.; Liebmann, M.; Walter, C.; Roth, S.; Aleth, H.; Börsch, A.-L.; Schmidt-Pogoda, A.; Beuker, C.; Yusuf, A. M.; Revenstorff, J.; Osei-Sarpong, C.; Krafft, L.; Schwarze, A.-S.; Heming, M.; Richter, M.; Kuhlmann, T.; Hucke, S.; Heming, J.-N.; Hansen, U.; Hagemann, N.; Bader, A.; Gao, J.; Walzog, B.; Maier-Begandt, D.; Chevre, R.; Hanschmann, E.-M.; Lücke, M.; Sommer, C.; Hermann, D. M.; Roth, J.; Thomas, C.; Meyer Zu Hörste, G.; Gunzer, M.; Vogl, T.; Zarbock, A.; Rosenbauer, F.; Silvestre-Roig, C.; Söhnlein, O.; Klotz, L.; Minnerup, J.
2025 bioRxiv
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Neutrophil Progenitor Mobilization Is a Distinct Feature of STEMI and Predicts SurvivalRichter, M.; Von Göwels*, J.; Fähndrich*, M.; Fernandez*, C. L.; Grohn*, K.; Schwarz, D.; Lang, A.; Polzin, A.; Farinola, L.; Gosh, S.; Groba, S. R.; Heming, J.-N.; Aleth, H.; Rübsamen, N.; Radecke, T.; Rosenbauer, F.; Sickmann, A.; Karch, A.; Zarbock, A.; Minnerup, J.; Sindermann, J.; Bender, A.; Rossaint, J.; Ormanns, S.; Gunzer, M.; Reinecke, H.; Makowski, L.; Jung, C.; Silvestre-Roig, C.; Kelm, M.; Gerdes, N.; Chevre, R.; Lange, S.; Soehnlein, O.
2025 Research Square
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Broad Rim Lesions Are a New Pathological and Imaging Biomarker for Rapid Disease Progression in Multiple SclerosisKlotz, L.; Smolders, J.; Lehto, J.; Matilainen, M.; Lütje, L.; Buchholz, L.; Albrecht, S.; Walter, C.; Varghese, J.; Wiendl, H.; Nylund, M.; Thomas, C.; Gardberg, M.; van den Bosch, A. M. R.; Airas, L.; Huitinga, I.; Kuhlmann, T.
2025 Nat Med
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Endurance Exercise Attenuates Established Progressive Experimental Autoimmune Encephalomyelitis and Is Associated with an Amelioration of Innate Immune Responses in NOD MiceSchiffmann, D.; Lampkemeyer, V.; Lindner, M.; Fleck, A.-K.; Koch, K.; Eschborn, M.; Liebmann, M.; Strecker, J.-K.; Minnerup, J.; Wiendl, H.; Klotz, L.
2023 Int J Mol Sci
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Neutrophils - Biology and DiversityMaier-Begandt, D.; Alonso-Gonzalez, N.; Klotz, L.; Erpenbeck, L.; Jablonska, J.; Immler, R.; Hasenberg, A.; Mueller, T. T.; Herrero-Cervera, A.; Aranda-Pardos, I.; Flora, K.; Zarbock, A.; Brandau, S.; Schulz, C.; Soehnlein, O.; Steiger, S.; the TRR332 consortium.
2023 Nephrol Dial Transplant
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Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on MonocytesRusso, A.; Schürmann, H.; Brandt, M.; Scholz, K.; Matos, A. L. L.; Grill, D.; Revenstorff, J.; Rembrink, M.; von Wulffen, M.; Fischer-Riepe, L.; Hanley, P. J.; Häcker, H.; Prünster, M.; Sánchez-Madrid, F.; Hermann, S.; Klotz, L.; Gerke, V.; Betz, T.; Vogl, T.; Roth, J.
2022 Advanced Science
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Neutrophils in aging and aging-related pathologiesVan Avondt, K.; Strecker, J.-K.; Tulotta, C.; Minnerup, J.; Schulz, C.; Soehnlein, O.
2022 Immunol Rev
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