Neuroinflammatory Mechanisms in Ischemic Stroke Pathophysiology

Ischaemic stroke initiates a complex injury cascade in which energy failure and excitotoxicity lead to neuronal death and release of damage-associated molecular patterns. These signals rapidly activate resident glial populations—microglia, astrocytes and oligodendrocyte precursor cells—resulting in a local inflammatory milieu. Concurrent disruption of the blood–brain barrier permits infiltration of peripheral leukocytes, including neutrophils, monocytes and lymphocytes, which further amplify cytokine and chemokine production. While acute neuroinflammation can exacerbate tissue damage through oxidative stress, matrix metalloproteinase activation and secondary haemorrhagic transformation, later phases of the response support debris clearance, angiogenesis and synaptic remodelling. A growing emphasis on cellular heterogeneity and time-dependent phenotypes has revealed both protective and detrimental roles for individual cell types. Dissection of the molecular cross-talk between glia and infiltrating myeloid cells, and identification of key mediators such as high-mobility group box 1 and osteopontin, are guiding the development of targeted therapies that seek to limit early injury while preserving or enhancing reparative processes.

Research from Nature Portfolio

Single-cell transcriptomic analysis of the acute ischaemic lesion in rodent models has uncovered distinct molecular programmes in oligodendrocyte lineage cells and astrocytes. Proliferating oligodendrocyte precursor cells and reactive astrocytes adopt subtype-specific signatures and engage in immuno-glial cross-talk with myeloid populations. In perilesional tissue, osteopontin-positive myeloid cells cluster alongside CD44-expressing glial cells, suggesting local signalling hubs that guide cell migration and fate. In parallel, selective ablation of microglia in vivo has demonstrated a neuroprotective role for these cells: their absence leads to exacerbated infarct size, dysregulated neuronal calcium handling and reduced incidence of spreading depolarisation, highlighting microglial regulation of excitotoxic injury and network stability after stroke.

Neuroinflammatory Mechanisms in Ischemic Stroke Pathophysiology publication trend

The graph below shows the total number of articles in neuroinflammatory mechanisms in ischemic stroke pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: Resident immune cells of the central nervous system that detect injury, phagocytose debris and secrete inflammatory mediators.

Astrocytes: Glial cells that maintain extracellular ion balance, support the blood–brain barrier and modulate synaptic activity.

Oligodendrocyte precursor cells (OPCs): Progenitor cells that differentiate into myelinating oligodendrocytes and contribute to tissue remodelling after injury.

High-mobility group box 1 (HMGB1): A damage-associated molecular pattern released by necrotic cells that triggers inflammation via pattern-recognition receptors.

Blood–brain barrier (BBB): A selective endothelial interface that regulates passage of cells and molecules between the circulation and the brain parenchyma.

Spreading depolarisation: A wave of near-complete neuronal and glial depolarisation that propagates through injured brain tissue, influencing infarct expansion.

References

1. Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents. Nature Communications (2024).
2. Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy. Journal of the American Chemical Society (2023).
3. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nature Communications (2016).
4. Neuroinflammation: friend and foe for ischemic stroke. Journal of Neuroinflammation (2019).