Complement-Mediated Mechanisms in Ischemic Stroke

The complement system, a central component of innate immunity, exerts a dual influence on cerebral ischaemia, driving both acute tissue injury and later reparative processes. Following arterial occlusion and reperfusion, complement activation is initiated via the classical, lectin and alternative pathways, leading to deposition of activation fragments such as C3b and the release of anaphylatoxins (C3a, C5a). These fragments promote endothelial activation, upregulate adhesion molecules and recruit neutrophils and monocytes into the ischaemic core and penumbra. Within the parenchyma, microglia and astrocytes respond to complement cues by adopting pro-inflammatory phenotypes, exacerbating neuronal death and blood–brain barrier breakdown. Conversely, complement components participate in synaptic remodelling, neurogenesis and angiogenesis during the subacute and chronic phases, supporting network reorganisation and functional recovery. The balance between harmful and protective effects depends on the timing, localisation and degree of complement engagement. Recent advances in targeted inhibition and timed activation of specific complement pathways underscore the therapeutic promise of modulating this system to limit early injury while preserving or enhancing later regenerative functions.

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Recent studies have clarified the context-dependent roles of C3a receptor signalling in post-stroke recovery. In rodent models, blockade of C3aR during the acute phase limits local inflammation, whereas intranasal administration of C3a from day seven post-stroke augments astrocyte-mediated repair and promotes white matter reorganisation, leading to accelerated motor function recovery and enhanced peri-infarct connectivity. Another line of investigation has delineated complement-mediated synaptic pruning as a contributor to post-stroke cognitive impairment. Excessive deposition of complement proteins on dendritic spines tags synapses for elimination by microglia and astrocytes, resulting in secondary network loss. Targeting this pathway may preserve synaptic integrity and limit cognitive deficits. Finally, work exploring common comorbidities has shown that ageing and cigarette smoke amplify complement activation in the ischaemic penumbra, aggravating neuroinflammation and functional decline. Penumbra-targeted complement inhibitors mitigate these exacerbating effects, reducing microglial activation and improving outcomes even in aged or smoking-exposed animals, highlighting the need to tailor complement-based therapies to patient risk profiles.

Complement-Mediated Mechanisms in Ischemic Stroke publication trend

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

Technical terms

Complement system: A cascade of plasma proteins that tags pathogens and damaged cells for clearance and generates inflammatory mediators.

Ischaemic stroke: A neurological event caused by blockage of cerebral blood flow resulting in tissue hypoxia and infarction.

Complement activation: Sequential proteolysis of complement proteins yielding opsonins, anaphylatoxins and membrane attack complexes.

Anaphylatoxin: Small complement fragments (C3a, C5a) that act as potent chemoattractants and inflammatory modulators.

Synaptic pruning: Elimination of excess or damaged synaptic connections by glial cells, critical for network refinement and plasticity.

Ischaemic penumbra: The peri-infarct region of threatened but potentially salvageable brain tissue following vessel occlusion.

References

1. Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity. Journal of Clinical Investigation (2023).
2. The Role of the Complement System in Synaptic Pruning after Stroke. Aging and Disease (2024).
3. Evaluating the comorbidities of age and cigarette smoking on stroke outcomes in the context of anti-complement mitigation strategies. Frontiers in Immunology (2023).