---
title: "Inflammation-focused Neurovascular–Immune–Metabolic Remodeling in Ischemic Stroke: Stage-Dependent"
id: "frontiers-in-immunology-14-inflammation-centered-neurovascular-immune-metabolic-remodeling-in-ischemic"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-14-inflammation-centered-neurovascular-immune-metabolic-remodeling-in-ischemic"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918327"
published_at: "2026-09-03T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Inflammation-focused Neurovascular–Immune–Metabolic Remodeling in Ischemic Stroke: Stage-Dependent
## Provenance & Clinical Metadata
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- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918327)
- **Published At:** 2026-09-03T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
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## Clinical Analysis & Structured Key Points
Frontiers | Inflammation-centered neurovascular–immune–metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation REVIEW article Front. Immunol. , 03 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1918327 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Part of a Research Topic Immunometabolism at the crossroads: Metabolic reprogramming and crosstalk in chronic diseases Submission open 12k views 10 articles Editor & Reviewers Edited by Z C Zhexu Chi Reviewed by B R Biqiong Ren A D Alexandre Dias Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article REVIEW article Front. Immunol. , 03 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1918327 Inflammation-centered neurovascular–immune–metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation L S Linjing Song 1 † Z S Zijin Sun 2 † X Z Xuhui Zhang 3 G S Guojiao Shang 2 S D Shanyu Du 4 F C Fafeng Cheng 2 * W X Wenxiu Xu 4 * 1. First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China 2. School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 3. School of Medicine, University of Health and Rehabilitation Sciences, Shandong, China 4. School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Shandong, China See more Article metrics View details Abstract Ischemic stroke evolves beyond arterial occlusion through an inflammation-centered network linking neurovascular dysfunction, immune remodeling, metabolic reprogramming, and regulated cell death. These interactions are organized across the hyperacute, acute, subacute, and chronic phases. Hyperacute energy failure, excitotoxicity, thromboinflammation, pericyte contraction, and capillary stalling can sustain microcirculatory no-reflow despite recanalization. Acute injury is characterized by blood–brain barrier disruption, innate immune amplification, mitochondrial stress, as well as ferroptotic, necroptotic, pyroptotic, and proposed cuproptotic pathways. Subacute recovery involves debris clearance, immune resolution, angiogenesis, metabolic adaptation, and oligodendrocyte-lineage repair, whereas chronic outcomes reflect persistent inflammation, white-matter remodeling, and neural plasticity. Cell-specific metabolism and brain-border and systemic immune–metabolic communication further shape injury and recovery. Experimental evidence is distinguished from findings in human blood, thrombectomy-derived samples, imaging, and brain tissue. Therapeutic translation requires stage-matched interventions compatible with reperfusion and rehabilitation, clinically realistic post-onset dosing, mechanistic biomarkers, and appropriate safety evaluation. This framework links early microvascular rescue with immune resolution, metabolic recovery, and network repair. 1 Introduction Ischemic stroke (IS) remains a major global cause of mortality and long-term disability ( 1 ). The Global Burden of Disease 2021 analysis shows that, although age-standardized stroke rates have declined in many settings since 1990, the absolute burden has continued to increase ( 1 , 2 ). China-specific analyses further illustrate substantial geographic heterogeneity ( 3 ). In current clinical practice, intravenous thrombolysis and mechanical thrombectomy improve outcomes in eligible patients ( 3 ), but access and benefit remain constrained by treatment eligibility and time. Reperfusion can also initiate a general ischemia–reperfusion injury cascade involving oxidative, inflammatory, and mitochondrial stress ( 4 ). Even after successful large-vessel recanalization, microcirculatory failure may persist: pericyte constriction can contribute to no-reflow ( 5 ), while damage-associated molecular patterns (DAMPs) can drive neutrophil extracellular trap (NET) formation, stabilize thrombi, impair thrombolysis, disrupt the blood–brain barrier (BBB), and amplify neuroinflammation ( 6 ). Tissue injury after IS extends far beyond the initial interruption of cerebral blood flow. Instead, it evolves as a progressive and highly interconnected pathological network involving BBB breakdown, oxidative stress, and robust neuroinflammatory activation ( 7 ). The infiltration and activation of diverse immune-cell populations within the brain parenchyma are tightly intertwined with disturbances in energy metabolism, collectively shaping the transition from acute injury to chronic remodeling ( 8 ). This pronounced clinical and biological heterogeneity, arising from the interplay among vascular pathology, metabolic failure, and immune responses, indicates that strategies focused solely on early vascular recanalization or single-target neuronal protection are insufficient to fully explain or address the complex pathological challenges that emerge after IS. Against this backdrop, the concept of neurovascular–immune–metabolic remodeling has emerged as an integrative framework for understanding IS. This concept refers to the coordinated and dynamic reorganization of resident cells within the central nervous system (CNS), key structural and functional components of the vascular microenvironment, and peripherally infiltrating immune cells at the transcriptional, metabolic, and spatial levels under ischemic–hypoxic stress ( 9 ). Rather than representing a simple aggregation of isolated cellular events, this process reflects a systems-level interaction network in which neuronal tissue injury, vascular barrier disintegration, immune-inflammatory activation, and energy metabolic reprogramming are causally interconnected and functionally integrated. Within this remodeling framework, the interplay between immune-cell state transitions and cellular metabolism constitutes a central hub that drives disease progression. Ischemia-induced bioenergetic crisis forces profound metabolic rewiring within the cerebral microenvironment. For example, the loss of mitochondrial metabolic flexibility in microglial and macrophage populations, together with enforced shifts in glycolipid metabolic pathways, directly shapes their phenotypic transition between proinflammatory neurotoxicity and tissue repair ( 10 , 11 ). Concomitantly, extensive intercellular communication networks further amplify this cross-system integration. Astrocytes not only undergo intrinsic metabolic remodeling to regulate BBB homeostasis and the neurotransmitter milieu ( 12 ), but also modulate the lipid metabolic trajectories and inflammatory response states of microglia through specific receptor–ligand interactions and paracrine signaling mechanisms ( 13 ). Vascular microenvironmental components, including endothelial cells and fibroblasts, likewise participate in the regulation of immune responses and the metabolic microecology through complex multicellular interactions. Inflammation is not an isolated downstream consequence of cerebral ischemia. It is a dynamic interface through which vascular dysfunction, immune-cell recruitment, glial activation, metabolic stress, and regulated cell death influence one another. Endothelial activation and BBB disruption promote leukocyte and platelet recruitment; activated immune and glial cells reshape local glucose, lactate, lipid, and amino-acid metabolism; and metabolite accumulation, mitochondrial dysfunction, and lipid peroxidation further amplify inflammatory signaling. These processes are strongly time-dependent and may shift from tissue-destructive to reparative functions as stroke evolves. Accordingly, this review uses inflammation as the organizing axis to integrate three closely connected dimensions of ischemic-stroke biology: neurovascular unit (NVU) and microcirculatory remodeling, local and systemic immune responses, and cell- and substrate-specific metabolic reprogramming. Within this framework, ischemia- and reperfusion-induced disturbances in communication among neurons, glial cells, vascular cells, circulating immune cells, and systemic metabolic organs are considered across the transition from early injury amplification to tissue containment, repair, and functional remodeling. Particular emphasis is placed on temporal and biological context, because the same cell population, metabolite, or inflammatory pathway may exert divergent or even opposing effects during the hyperacute, acute, subacute, and chronic phases. The discussion focuses on convergent mechanisms linking vascular dysfunction, immune activation, metabolic failure, and regulated cell death, rather than on an exhaustive catalogue of signaling molecules or experimental compounds. Findings from experimental models are interpreted alongside available human evidence, with attention to stroke etiology, reperfusion status, aging, and common metabolic comorbidities. This inflammation-centered and temporally resolved framework provides a basis for identifying the principal determinants of injury and recovery, evaluating barriers to clinical translation, and defining therapeutic opportunities that require stage-specific and biologically stratified intervention. 2 Stage-dependent evolution of ischemic injury and remodeling 2.1 Hyperacute phase: energy failure and injury initiation During the hyperacute phase of IS, abrupt interruption of cerebral blood flow rapidly deprives the brain of oxygen and glucose, impairing neuronal mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production. Loss of ion-pump function then drives membrane depolarization, glutamate release, ionic disequilibrium, and calcium overload. Mechanistic syntheses describe this as a continuous cascade linking bioenergetic failure, excitotoxicity, oxidative stress, regulated cell death, and mitochondrial dysfunction ( 4 , 14 ). Metabolomic studies likewise connect disturbances in glutamate metabolism and the tricarboxylic acid cycle with oxidative stress, inflammation, and energy failure ( 15 ). Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and voltage-dependent calcium channels increases intracellular Ca 2+ , which promotes mitochondrial dysfunction, endoplasmic reticulum stress, reactive oxygen species (ROS) generation, and calcium-dependent injury pathways ( 16 , 17 ). As a critical hub for energy metabolism and cell-death regulation, mitochondria exhibit early reductions in membrane potential, impaired bioenergetic capacity, and heightened oxidative stress after ischemic insult ( 18 ). When damaged mitochondria are not efficiently removed, mitochondrial dysfunction and oxidative injury can form a self-amplifying pathological loop ( 19 ). In addition, aberrant activation of transient receptor potential melastatin channels and uncoupling of neuronal nitric oxide synthase may further aggravate early neuronal injury by promoting calcium overload, ROS generation, mitochondrial damage, and energy loss ( 20 , 21 ). Thus, hyperacute ischemic injury is not merely a consequence of oxygen deprivation. Rather, it begins with metabolic collapse and rapidly connects ionic disequilibrium, excitotoxicity, calcium overload, and mitochondrial injury, thereby establishing the pathological foundation for subsequent neurovascular–immune–metabolic remodeling. 2.2 Acute phase: barrier failure and inflammatory amplification As ischemia–reperfusion progresses into the acute phase, NVU injury is initially manifested by endothelial damage and loss of barrier stability. The endothelial cell-derived arachidonate 12-lipoxygenase (ALOX12)–12-hydroxyeicosatetraenoic acid (12-HETE) axis is upregulated after cerebral ischemia–reperfusion, impairing tight junction integrity while concomitantly promoting proinflammatory microglial activation and oxidative neuronal injury ( 22 ). Overexpression of nicotinamide adenine dinucleotide phosphate oxidase 5 (NOX5) similarly aggravates ischemia-associated neuroinflammation by altering endothelial junctional architecture, increasing vascular permeability, and facilitating immune-cell adhesion and infiltration ( 23 ). Thus, acute BBB disruption is not merely a passive structural failure. Rather, it represents a dynamic process driven by endothelial oxidative stress, cytoskeletal remodeling, and degradation of tight junction proteins. The pathological increase in BBB permeability creates a permissive route for peripheral immune cells to enter the brain parenchyma, thereby establishing a self-reinforcing inflammatory loop with locally activated microglia. Microglial activation, neutrophil infiltration, and the release of proinflammatory cytokines collectively exacerbate BBB breakdown and neuronal death, whereas BBB injury further facilitates immune-cell entry and inflammatory dissemination ( 24 ). In patients with acute IS, elevated serum levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3) and occludin are associated with infarct volume, National Institutes of Health Stroke Scale (NIHSS) scores, hemorrhagic transformation, and poor clinical outcomes, suggesting a clinically relevant link between inflammasome activation and tight junction injury ( 25 ). Experimental evidence further indicates that serum amyloid A (SAA) signaling can induce inflammation, glial activation, and increased BBB permeability through NLRP3-dependent mechanisms ( 26 ). Inflammatory amplification during the acute phase also involves the gliovascular unit and peripheral thromboinflammatory signals. After ischemic injury, perivascular upregulation of secreted phosphoprotein 1 (SPP1) is accompanied by enhanced microglial synaptic engulfment, aggravated neuroinflammation, and impaired BBB integrity ( 27 ). NET formation further disrupts vascular integrity through protease activity, inflammatory signaling, and microvascular obstruction, with translational and experimental studies linking NETs to brain injury, resistance to thrombolysis, and impaired vascular repair ( 28 – 30 ). Fibrinogen can also bind integrin subunit beta 2 (ITGB2) on microglia and activate JAK–STAT signaling, thereby altering microglial function while aggravating BBB disruption and neuroinflammation ( 31 ). Collectively, BBB breakdown, immune-cell infiltration, microglial activation, and inflammatory-mediator release form a self-amplifying acute injury cascade. 2.3 Subacute phase: immune resolution and repair initiation Across the acute-to-subacute transition, the inflammatory response undergoes a dynamic transition from acute tissue injury toward reparative remodeling. At this stage, large numbers of peripheral monocytes are recruited into the injured brain and differentiate into MDMs. These cells serve a central clearance function by phagocytosing necrotic neurons and myelin debris, while simultaneously activating lysosomal- and lipid metabolism-associated gene programs that define highly phagocytic Cd68hi/Ctsdhi subsets ( 32 ). MDMs also exhibit phenotypic adaptation during the subacute phase, shifting from an early inflammation-associated state toward a microglia-like phenotype. This transition is accompanied by enhanced phagocytic activity and provides a cellular basis for debris removal and inflammatory resolution within injured tissue ( 33 ). Across the acute-to-subacute transition, microglia display marked functional plasticity. Itgb2+ microglial subsets participate in energy metabolism, cell-cycle regulation, angiogenesis, and myelination at days 1, 3, and 7 after ischemic injury, respectively ( 34 ). In an interleukin-4 (IL-4)-conditioned mouse transient middle cerebral artery occlusion (MCAO) paradigm, microglial extracellular vesicles (EVs) enriched in miR-23a-5p promoted oligodendrocyte precursor cells (OPCs) proliferation, survival, and differentiation and supported white-matter repair ( 35 ). Regulatory T cells (Tregs)-derived osteopontin can strengthen reparative microglial functions through integrin receptors and facilitate OPCs differentiation and white-matter regeneration ( 36 ). Local BBB-associated chemokines and neuropeptides, including pituitary adenylate cyclase-activating polypeptide, may likewise favor repair-supporting microglial functions in experimental models ( 37 ). Fibrotic remodeling and vascular regeneration are likewise integral components of subacute repair. In IL-4-conditioned experimental systems, macrophages promoted meningeal-fibroblast proliferation, migration, and extracellular matrix (ECM) production through the PU.1/mTOR axis ( 38 ). In a rat MCAO/reperfusion model, IL-4-conditioned macrophages promoted early fibrotic-scar formation through transforming growth factor beta 1 (TGF-β1) and matrix metalloproteinase (MMP)-9, with concurrent angiogenic and functional changes ( 39 ). An enriched environment can also reduce microglia-associated proinflammatory cytokine production and support white-matter regeneration ( 40 ). These findings show that beneficial inflammatory functions depend on cellular state, timing, and phagocytic competence rather than on a fixed binary macrophage label. 2.4 Chronic phase: network reconstruction and functional recovery During the chronic phase of IS, the neurovascular–immune–metabolic network is progressively reorganized and maintained in a dynamic equilibrium. At this stage, inflammation is not uniformly detrimental; rather, when properly regulated, it contributes to tissue repair and functional restoration. Microglia exhibit diverse phenotypic states during chronic remodeling, and their interactions with neurons, astrocytes, and endothelial cells shape neural plasticity and synaptic reorganization. Through the secretion of soluble mediators and EVs, microglia also regulate the local inflammatory milieu and BBB integrity ( 41 , 42 ). OPCs acquire an oligodendrogenic state during the chronic phase and contribute to white-matter repair and remyelination, with their function being influenced by local oxygen tension and the vascular microenvironment ( 43 ). Endothelial cells likewise display stage-specific differentiation and enhanced anti-inflammatory signaling, thereby regulating vascular homeostasis and promoting microvascular angiogenesis. In parallel, endothelial adhesion molecules selectively guide lymphocyte infiltration and support neurovascular repair ( 44 ). Neural plasticity and synaptic remodeling involve endogenous neural stem cells and glial–neuronal interactions. Experimental transcription-factor-mediated astrocyte-to-neuron reprogramming has generated neuron-like cells in rodent cortex and striatum and has been associated with functional improvement, but lineage fidelity, reproducibility, and clinical feasibility remain unresolved ( 45 , 46 ). Pericytes and endothelial cells support microvessel formation through vascular endothelial growth factor (VEGF)- and microRNA (miRNA)-related mechanisms ( 47 ). Reactive astrocytes can contribute to scar organization and lesion containment, whereas other astrocyte states provide trophic and platelet-derived growth factor (PDGF)-related support for axonal and vascular remodeling; these functions vary with time, region, and transcriptional state ( 48 ). Chronic recovery therefore reflects coordinated neural plasticity, angiogenesis, white-matter repair, and scar remodeling, while persistent low-grade inflammation may remain in selected models and patient subsets ( Figure 1 ). Figure 1 Stage-dependent evolution of neurovascular-immune-metabolic remodeling after ischemic stroke. The four color-coded columns (dark magenta, hyperacute; violet, acute; blue, subacute; and green, chronic) depict the overlapping progression of post-ischemic injury and repair, with gray arrows indicating movement across phases. In the hyperacute phase, vessel occlusion initiates ATP depletion, excitotoxicity, Ca 2+ overload, mitochondrial dysfunction, ROS production, and
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