International Journal of Molecular Sciences

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Brain–Immune Crosstalk and Ischemic Injury

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Dr. Yvonne Couch

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Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Interests: neuroimmunology; CNS metabolism; brain–immune communication; extracellular vesicles

Special Issue Information

Dear Colleagues,

This Special Issue aims to focus on the dynamic interactions between the central nervous system and the immune system in the context of ischemic injury. We aim to explore how immune responses influence brain damage and recovery following ischemic events, such as stroke, and how neural signals modulate systemic and local immune activity.

We aim to collate cutting-edge research elucidating the mechanisms of brain–immune crosstalk in ischemic injury, highlighting translational insights that could inform novel therapeutic strategies for neuroprotection, inflammation modulation, and functional recovery.

Potential topics of interest include the following:

Innate and adaptive immune responses following cerebral ischemia or haemorrhage;
Microglia and astrocyte contributions to post-ischemic inflammation;
Peripheral immune cell trafficking to the brain after stroke;
Cytokine and chemokine signalling in ischemic injury;
Neurovascular unit disruption and immune interactions;
Immune modulation as a therapeutic approach for ischemic injury;
Biomarkers linking immune activity to stroke severity and outcomes;
Neuroimaging and spatial mapping of immune activity post-ischemia;
Sex differences and age-related variations in brain–immune responses;
Preclinical models vs. human studies of post-ischemic immune dynamics.

Dr. Yvonne Couch
Guest Editor

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Research

24 pages, 6541 KB

Open AccessArticle

Differential Effects of Ischemia and Inflammation on Plasma-Derived Extracellular Vesicle Characteristics and Function in a Mouse Model

by Yvonne Couch

Int. J. Mol. Sci. 2026, 27(4), 1762; https://doi.org/10.3390/ijms27041762 - 12 Feb 2026

Viewed by 488

Abstract

Extracellular vesicles (EVs) have long been understood to be important mediators of cell-to-cell communication and may lead to the molecular aftermath and exacerbation of brain injuries such as stroke. This study explored how the source of the EVs influenced their characteristics and the effect these differences had on naïve brain tissue. EVs were isolated from mice post-stroke in the acute or chronic stages of recovery in animals with and without reperfusion (transient and permanent middle cerebral artery occlusion) and from a model of systemic inflammation (i.p. lipopolysaccharide). The data show that neither stroke nor inflammation significantly increases EV numbers compared to sham or naïve animals. Post-stroke EVs exhibited a panel of different platelet and inflammatory markers when compared to EVs derived from a model of inflammation, reflecting differences between stroke and systemic immune activation. When injected into the brain, both stroke-derived and inflammation-derived EVs induced pro-inflammatory cytokine gene expression (IL-1β and CXCL1), suggesting a potential role in neuroinflammation. However, no clear group-level differences in microglial or astrocytic reactivity were detected at the level of regional histological assessment, despite consistent increases in ICAM-1 reactivity. The findings here underscore the complexity of EVs’ roles in pathophysiology and highlight the need for improved EV isolation methods. With further longitudinal studies, we may be able to more accurately determine how the context of the injury (reperfusion vs. no reperfusion vs. inflammation) might contribute to the EV populations and their function. Understanding more about EVs in different contexts will improve our ability to use EVs as biomarkers but also our capacity to interfere with EV biology as a novel therapeutic approach. Full article

(This article belongs to the Special Issue Brain–Immune Crosstalk and Ischemic Injury)

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18 pages, 1338 KB

Open AccessArticle

Lack of Negative Feedback Loops of CTLA-4 and PD-L1 as Key Mechanisms for Post-Acute T Cell Activation Until 3 Months After Ischemic Stroke

by Lars Peglau, Johanna Ruhnau, Mara Winkelmann, Thomas Krüger, Alexander Dressel, Juliane Schulze and Antje Vogelgesang

Int. J. Mol. Sci. 2025, 26(23), 11489; https://doi.org/10.3390/ijms262311489 - 27 Nov 2025

Cited by 1 | Viewed by 576

Abstract

Post-stroke T lymphocytes exert differential effects both at the infarction site and systemically; these are pro-inflammatory cascades, subsequent T cell infiltration into the brain, and persisting interaction of infiltrating T lymphocytes (more specifically a subset of CD4- CD8-double-negative T cells (DNTs)). Moreover, brain-resident microglia cells exacerbate the parenchymal damage. The acute peripheral immune response is characterized by lymphopenia and persisting activation of circulating T lymphocytes. In the temporal course, it is supposed that anti-inflammatory mechanisms in general and especially the anti-inflammatory M2 phenotype of microglia cells help to recover the functionality of brain parenchyma. We assessed the long-term temporal course of peripheral blood T cell activation post stroke as well as the interaction of pan-T cells or DNTs with microglia cells ex vivo. T cell subpopulations (CD4⁺, CD8⁺, DNT) and their activation (CD25, CD57, CTLA-4 (CD152) and PD-L1 (CD274)) were analysed in peripheral blood from stroke patients and controls by flow cytometry. Pan-T cells and DNTs were isolated by magnetic beads from stroke patients’ blood 3 days (t₁), 1 month (t₂), and 3 months (t₃) post stroke or once from controls, and they were incubated with or without healthy donor human microglia cells ex vivo. Upon interaction, T cell (HLA-DR) and microglia activation (HLA-DR, CX3CR1, CD32, CD86, CD206 and CD209) was assessed by flow cytometry. Moreover, IL-1β in cell culture supernatants was quantified by ELISA. Post-stroke CD4⁺ and CD8⁺ T cell activation (CD25) persisted for 1 month and declined only after 3 months. Inhibitory activation markers CTLA-4 and PD-L1 were upregulated only 3 months after stroke. Co-culture of pan-T cells and microglia had little effect on microglial activation but a strong effect on T cell activation (HLA-DR). Co-culture of DNTs with microglia cells inhibited the M2 phenotype of microglia. Stroke acutely leads to a strong activation (CD25 upregulation) of both CD4⁺ and CD8⁺ T cells. This activation persisted in the subacute post-stroke phase and declined at 3 months post stroke, being accompanied by upregulation of PD-L1 and CTLA-4. Both might be involved in terminating chronic T cell activation. DNTs might influence microglia through CX3CR1 and inhibit an M2 state ex vivo, which might contribute to cerebral inflammation post stroke. Full article

(This article belongs to the Special Issue Brain–Immune Crosstalk and Ischemic Injury)

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