Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.image Abstract figure legend A demonstrates the human body with an underlying normal sinus rhythm traversing into ventricular fibrillation to signify cardiac arrest. B reveals the anatomical structures and cell types pertinent to the neurovascular unit. A cerebral capillary is shown with surrounding astrocytes and adjacent neuronal cell bodies with projecting axons. Leucocyte adhesion and extravasation through the blood-brain barrier is demonstrated, with subsequent differentiation into macrophages and release of pro-inflammatory cytokines. Additionally, pro-inflammatory cytokines are shown to be secreted from microglia, resulting in axonal injury and degeneration. C reveals the sequential events that lead to leucocyte adhesion to the endothelium, extravasation and migration into the brain tissue. Key molecules, such as E- and P-selectin, facilitate leucocyte adhesion and migration. D demonstrates the three pathways of the complement cascade, i.e. the classical, lectin and alternative pathways. Each pathway converges on C3, with activation into C3a and C3b. Subsequent recruitment of leucocytes and splitting of C5 into active forms results in downstream amplification of the complement cascade. E depicts the role of reactive astrocytes and microglia in propagation of the inflammatory cascade by releasing pro-inflammatory cytokines into the brain parenchyma. Subsequent injury to healthy neurons results in pyroptosis.image

Automated summary

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with the response of the innate immune system, including pro-inflammatory cytokines, leucocyte migration and activation, and complement cascade. Inhibiting an immunopathological response may be an effective therapeutic strategy.