Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke

Abstract

Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1−/− mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.

Serpin family proteins as potential biomarkers and therapeutic drugs in stroke: A systematic review and meta‐analysis on clinical/preclinical studies

“…A recent study reported that intranasal delivery of serpina3n, the mouse homolog of human α1‐ACT, reduced infarct size and rescued neurological deficits after stroke. Similarly, it attenuated BBB disruption by suppressing immune cell infiltration into the brain 60 . Besides, our meta‐analysis indicated that α1‐antitrypsin level was higher in both IS and HS patients though, it reduced the infarct size in MCAO models ( p = 0.23).…”

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.…”

“…54 Consistently, a recent study reported that Serpina3n was predominantly upregulated in neurons within the infarct and penumbra areas of tMCAO-injured mouse brain; global Serpina3n KO or AAV-mediated neuron-specific Serpina3n KD aggravated immune cells infiltration. 53 Taken together, these preclinical animal data lead to an alternative hypothesis that neuron-derived Serpina3n counteracts neuroinflammation in ischaemic brain injury. AAV particles are systemically delivered.…”

“…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.…”