Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

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.

microRNA‐9‐5p alleviates blood–brain barrier damage and neuroinflammation after traumatic brain injury

“…According to the pathological process, TBI can be divided into two stages: the primary injury which is caused by external force, and the secondary injury which is caused by a series of pathophysiological changes in neurochemistry, metabolism, cells, and molecules (Amorini et al, ; Di Pietro et al, ). The secondary brain injury mainly includes excessive inflammatory response and blood–brain barrier (BBB) breakdown (Liu et al, ). Following TBI, microglia were activated and released a large number of inflammatory factors including IL‐1, IL‐6, and TNF‐α, which can destroy the blood–brain barrier and induce cellular apoptosis (Chen, Zhu, Hang, & Wang, ).…”

Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

“…133 ANXA2 may also control the pro-inflammatory response in resident microglia by modulating IL-17 signaling as well as ROS production. 134 Additionally, annexin A1 (ANXA1) was shown to be a regulator of microglia activation in the BV-2 microglia cell line under oxygen/glucose deprivation conditions. 135 In this study, the effect of ANXA1 on microglia was shown to be mediated by formyl peptide receptors (FPRs).…”

Annexin Animal Models—From Fundamental Principles to Translational Research

“…On the other hand, lentiviral AnxA2 receptor overexpression suppressed neovascularization in the mouse aortic ring and matrigel plug assays [ 145 ]. The role of AnxA2 in vascular homeostasis extends to endothelial permeability and integrity at the blood–brain barrier after cerebrovascular injury, with AnxA2-deficient mice displaying increased inflammation and reduced expression of cerebral endothelial junctional proteins [ 146 , 147 ]. For further reading of AnxA2-related aspects in vascular homeostasis and angiogenesis we recommend several excellent reviews [ 115 , 116 , 119 , 120 , 121 , 142 ] ( Table 2 c).…”