Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia

Abstract Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients, we show that stroke-associated pneumonia is associated with poor clinical outcome and long-term neutrophil deregulation. In mice exposed to transient middle cerebral artery occlusion (MCAO), experimental S. pneumoniae pneumonia induced at 3 days after stroke impaired neurological recovery and increased blood–brain barrier breakdown, brain neutrophil infiltrates, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Proteome analysis revealed that pneumonia induced a degranulation, platelet activation, and NETosis signature in peripheral blood neutrophils of MCAO mice, which was partly reversed by amoxicillin treatment. Subsequent studies showed that neutrophils were critical mediators of pneumonia-associated blood–brain barrier breakdown and microvascular thrombosis. Notably, administration of an antibody neutralizing extracellular histone proteins during pneumonia reduced ischemic injury, restored neurological recovery and prevented long-term brain atrophy in stroke-associated pneumonia mice. These protective effects were not observed after degradation of neutrophil extracellular traps by DNase-I, blockade of neutrophil extracellular trap formation by LDC7559 or myeloperoxidase inhibition by AZD4831, when these treatments were administered on occasion of pneumonia. This study identifies extracellular histones as key drivers of inflammatory brain injury and establishes histone neutralization as a strategy that protects against the deleterious effects of pneumonia after stroke.

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Publication Details

Journal
Acta Neuropathologica
Published
2026-10-09
DOI
https://doi.org/10.1007/s00401-026-03097-0
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
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article

Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia

Benedikt Frank, Ertuğrul Kılıç, Stephanie Thiebes, Devon Siemes et al.
Acta Neuropathologica
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
article

Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia

Benedikt Frank, Ertuğrul Kılıç, Stephanie Thiebes, Devon Siemes, Matthias Gunzer, Ali Ata Tuz, Jonas Raspe, Janine Gronewold, Britta Kaltwasser, Olga Shevchuk, Anran Li, Nina Hagemann, Bente Siebels, Tobias Tertel, Daniel Robert Engel, Bayram Yılmaz, Jens Minnerup, Vikramjeet Singh, Dongpei Yin, Claudia Graser, Humeyra Tas, Luisa Klotz, Hartmut Schlüter, Fengyan Jin, Ekaterina Pylaeva, Egor Dzyubenko, Jadwiga Jablonska, Dirk M. Hermann, Michael Fleischer, Yiqiao Zhang, Ayan Mohamud Yusuf, Bernd Giebel, Michaela Schedel, Oliver Soehnlein, Chen Wang, Yi Liu
article en

Abstract

Abstract Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients, we show that stroke-associated pneumonia is associated with poor clinical outcome and long-term neutrophil deregulation. In mice exposed to transient middle cerebral artery occlusion (MCAO), experimental S. pneumoniae pneumonia induced at 3 days after stroke impaired neurological recovery and increased blood–brain barrier breakdown, brain neutrophil infiltrates, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Proteome analysis revealed that pneumonia induced a degranulation, platelet activation, and NETosis signature in peripheral blood neutrophils of MCAO mice, which was partly reversed by amoxicillin treatment. Subsequent studies showed that neutrophils were critical mediators of pneumonia-associated blood–brain barrier breakdown and microvascular thrombosis. Notably, administration of an antibody neutralizing extracellular histone proteins during pneumonia reduced ischemic injury, restored neurological recovery and prevented long-term brain atrophy in stroke-associated pneumonia mice. These protective effects were not observed after degradation of neutrophil extracellular traps by DNase-I, blockade of neutrophil extracellular trap formation by LDC7559 or myeloperoxidase inhibition by AZD4831, when these treatments were administered on occasion of pneumonia. This study identifies extracellular histones as key drivers of inflammatory brain injury and establishes histone neutralization as a strategy that protects against the deleterious effects of pneumonia after stroke.

Acta NeuropathologicaVol. 152(1)
Universität Hamburg (DE), Dokuz Eylül University (TR), University of Münster (DE), Ruhrlandklinik (DE), University Hospital Münster (DE), Dalian Municipal Central Hospital (CN), University Medical Center Hamburg-Eppendorf (DE), University Hospital Schleswig-Holstein (DE), Essen University Hospital (DE), Leibniz Institute for Analytical Sciences - ISAS (DE), First Hospital of Jilin University (CN), German Centre for Cardiovascular Research (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Istanbul Medeniyet University (TR), University of Duisburg-Essen (DE), University of Lübeck (DE)
Openalex Percentile: Top 20%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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