REVIEW article
Front. Immunol.
Sec. Systems Immunology
This article is part of the Research TopicInflammation as a fundamental mechanism of strokeView all articles
From Disruption to Remodeling: The Evolution and Therapeutic Prospects of Neuroimmune Regulatory Circuitry after Ischemic Stroke
Provisionally accepted
- Renmin Hospital of Wuhan University, Wuhan, China
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Ischemic stroke (IS) is a leading cause of death and long-term disability globally, and the efficacy of current reperfusion therapies is limited, highlighting a significant unmet clinical need. This review reconceptualizes IS not as a mere focal brain injury but as a systemic disease driven by the catastrophic collapse of the Neuroimmune Regulatory Circuitry. This sophisticated network, normally responsible for maintaining homeostasis, undergoes a multi-level failure after stroke, beginning with pathological sensory input and culminating in a dysregulated efferent response characterized by sustained sympathetic hyperactivity and Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction. These aberrant neural commands pathologically alter the phenotype and function of peripheral immune cells, leading to a profound immune imbalance: emergency hematopoiesis generates primed, pro-inflammatory myeloid cells, while the lymphoid lineage suffers massive depletion through apoptosis and sequestration, causing severe lymphopenia. This framework unifies seemingly disparate post-stroke complications—such as Stroke-Induced Immunosuppression (SIIS) and subsequent infections, long-term cardiovascular events fueled by chronic inflammation, and cognitive decline driven by persistent neuroinflammation—as predictable outcomes of this circuitry failure. Consequently, this review argues for a paradigm shift away from single-target therapies towards an "integrative and sequential" approach to treatment. Future strategies should aim to recalibrate this entire circuit, leveraging biomarkers to overcome patient heterogeneity and applying temporally-dependent interventions that inhibit acute injury while promoting chronic repair. This provides a more rational foundation for developing effective neuroprotective and restorative therapies for stroke patients.
Keywords: ischemic stroke, Neuroimmune Regulatory Circuitry, neuroimmunology, Sympathetic Nervous System, Vagus Nerve
Received: 09 Sep 2025; Accepted: 19 Dec 2025.
Copyright: © 2025 Gao, Chen, Tao, Han, Zhu and Gu. 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:
Zhanyong Zhu
Lijuan Gu
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