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BRIEF RESEARCH REPORT article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1502346
This article is part of the Research Topic The Role of Inflammation in Organ Injury View all 9 articles

Hypercholesterolemia triggers innate immune dysbalance and transforms brain infarcts after ischemic stroke

Provisionally accepted
Vikramjeet Singh Vikramjeet Singh 1*Ali Ata Tuz Ali Ata Tuz 2Nils Hoerenbaum Nils Hoerenbaum 2Özgür Ulusoy Özgür Ulusoy 2Adel Ahmadi Adel Ahmadi 2Alana Gerlach Alana Gerlach 2Alexander Beer Alexander Beer 2Andreas Kraus Andreas Kraus 2Anja Hasenberg Anja Hasenberg 2Nina Hagemann Nina Hagemann 3Dirk M. Hermann Dirk M. Hermann 3Matthias Gunzer Matthias Gunzer 2
  • 1 University of Duisburg-Essen, Duisburg, Germany
  • 2 Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, Essen, North Rhine-Westphalia, Germany
  • 3 Department of Neurology, University Hospital Essen, University of Duisburg-Essen, DE-45147 Essen, Germany

The final, formatted version of the article will be published soon.

    Post-stroke early activation of neutrophils contributes to intensive neuroinflammation and worsens disease outcomes. Other pre-existing patient conditions can modify the extent of their activation during disease, especially hypercholesterolemia. However, whether and how increased circulating cholesterol amounts can change neutrophil activation responses very early after stroke has not been studied. In this study, we investigated the effect of high-fat diet (HFD) induced hypercholesterolemia on neutrophil activation and stroke outcome. Mice were fed with HFD or normal diet (ND) for six weeks and then induced stroke by transient occlusion of the middle cerebral artery. The activation receptors on immune cells and plasma levels of cytokines were analyzed using flow cytometry. The amount of plasma neutrophil extracellular traps (NETs) was measured using citH3-DNA complex ELISA. We found that HFD-induced cholesterolemia increased the number of circulating and splenic neutrophils in stroke mice but reduced bone marrow neutrophils compared to sham controls. After stroke neutrophils in HFD mice expressed higher levels of activation markers Ly6G and PSGL-1 (CD162) compared to ND mice. In addition, stroke led to an increased expression of the activation markers Ly6C and CD68 on monocyte/macrophages (MΦ) in HFD mice but not in ND mice. Compared to ND, HFD increased plasma levels of the proinflammatory cytokines TNF-a, IL-6, IL-23, and MCP-1. Remarkably, HFD mice showed higher amounts of circulating NETs, brain-infiltrated neutrophils, and larger infarcts after stroke compared to ND mice. The existence of hypercholesterolemia with a stroke can trigger a stronger activation of neutrophils and MΦ, causing deteriorating disease outcomes.

    Keywords: high-fat diet, Hypercholesterolemia, Stroke, Neutrophils, Inflammation

    Received: 26 Sep 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Singh, Ata Tuz, Hoerenbaum, Ulusoy, Ahmadi, Gerlach, Beer, Kraus, Hasenberg, Hagemann, Hermann and Gunzer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Vikramjeet Singh, University of Duisburg-Essen, Duisburg, Germany

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