Abstract
Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.
Highlights
Pro-inflammatory responses at the acute phase after traumatic brain injury (TBI) are characterized by elevated pro-inflammatory cytokines produced by activated microglia, astrocytes, and infiltrated peripheral inflammatory cells, which cause blood–brain barrier (BBB) permeability and neurotoxicity, thereby worsening outcomes [1,2,3]
Our result showed that A2 knockout (A2KO) had significantly larger brain tissue loss compared to WT mice (21% increase) (Figure 6), indicating that A2KO worsens brain tissue damage compared to WT mice after TBI
The major experimental findings of the present study can be summarized: (1) Annexin A2 (AnxA2) expression was significantly up-regulated in response to TBI; (2) compared with WT mice, A2KO mice displayed was significantly up-regulated in response to TBI; (2) compared with WT mice, A2KO mice displayed a significant increase of leukocyte brain infiltration and expression for pro-inflammatory cytokines a significant increase of leukocyte brain infiltration and expression for pro-inflammatory cytokines and adhesion molecules in the ipsilateral brain after TBI; (3) the A2KO mice had significantly worse neurological function deficits and increased brain tissue loss compared to the WT controls after TBI
Summary
Pro-inflammatory responses at the acute phase after traumatic brain injury (TBI) are characterized by elevated pro-inflammatory cytokines produced by activated microglia, astrocytes, and infiltrated peripheral inflammatory cells, which cause blood–brain barrier (BBB) permeability and neurotoxicity, thereby worsening outcomes [1,2,3].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
