Downregulation of Sepina3n Aggravated Blood–Brain Barrier Disruption after Traumatic Brain Injury by Activating Neutrophil Elastase in Mice

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

“…27 Recent in vivo data have shown that Serpina3n upregulation in neurons mitigated neuronal injury and loss in ischaemic and traumatic brain injury. [53][54][55]61 These studies suggest that neuronal induction of Serpina3n may represent an endogenous adaptive mechanism to ischaemic and traumatic brain injury. Interestingly, the downstream targets underlying Serpina3n-regulated neuronal viability seem to be injury-type dependent.…”

“…Neuron-derived Serpina3n was reported to exert a protective role against BBB damage in ischaemic brain injury 53 and traumatic brain injury. 55 In contrast, astrocyte-derived Serpina3n/SERPINA3 appeared to cause BBB dysfunction in an iPSC-derived BBB co-culture model and the homeostatic mouse brain. 63 Again, these studies failed to consider the potential role of peripheral circulating Serpina3n/SERPINA3 in BBB impairment.…”

“…Interestingly, the downstream targets underlying Serpina3n-regulated neuronal viability seem to be injury-type dependent. Serpina3n was reported to promote neuronal survival through inhibiting granzyme B 27,53 or clusterin 54 in ischaemic brain injury, whereas it promoted neuronal survival in traumatic brain injury by inhibiting leukocyte elastase 55 or matrix metalloproteinase 2 (MMP2), 61 but not granzyme B. In sharp contrast, astrocytederived Serpina3n was shown to aggravate neuronal injury and death in chemical-induced neurotoxic injury 60 and epileptic injury 64 presumably through promoting neuroinflammation as discussed above.…”

“…Altogether, these data challenge the long‐held concept that Serpina3n is dysregulated primarily in reactive astrocytes in the diseased/injured or aged CNS. Further challenging the widely cited concept, 44 the latest studies reported that Serpina3n protein was upregulated primarily in neurons of the acute lesion cores of ischaemic 53,54 and traumatic brain injury 55 (Table 2). Taken together, this evidence indicates that it is necessary to revisit the concept of Serpina3n as a marker of reactive astrocytes at the mRNA and protein levels.…”

Cerebrospinal fluid proteomics in meningitis patients with reactivated varicella zoster virus

“…Sun et al 27 found that the levels of serum neutrophilic elastase in patients with influenza encephalopathy were significantly higher than those in patients with uncomplicated influenza, suggesting that brain endothelial injury during the development of influenza was mediated by neutrophilic elastase. A traumatic experiment in a mouse model also suggests that inhibiting the activity of neutrophil elastase can reduce secondary blood–brain barrier damage 28 . Rugemalira et al observed a high MPO activation in CSF in children with bacterial meningitis as compared to those of nonbacterial meningitis and also found that activated MPO can be used as a biomarker for grading inflammation severity 29 .…”