Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice

Abstract

BackgroundNetrin-1 functions largely via combined receptors and downstream effectors. Evidence has shown that astrocytes express netrin-1 receptors, including DCC and UNC5H2. However, whether netrin-1 influences the function of astrocytes was previously unknown.MethodsLipopolysaccharide was used to stimulate the primary cultured astrocytes; interleukin release was used to track astrocyte activation. In vivo, shRNA and netrin-1 protein were injected in the mouse brain. Infarct volume, astrocyte activation, and interleukin release were used to observe the function of netrin-1 in neuroinflammation and brain injury after middle cerebral artery occlusion.ResultsOur results demonstrated that netrin-1 reduced lipopolysaccharide-induced interleukin-1β and interleukin-12β release in cultured astrocytes, and blockade of the UNC5H2 receptor with an antibody reversed this effect. Additionally, netrin-1 increased p-AKT and PPAR-γ expression in primary cultured astrocytes. In vivo studies showed that knockdown of netrin-1 increased astrocyte activation in the mouse brain after middle cerebral artery occlusion (p < 0.05). Moreover, injection of netrin-1 attenuated GFAP expression (netrin-1 0.27 ± 0.06 vs. BSA 0.62 ± 0.04, p < 0.001) and the release of interleukins and reduced infarct volume after brain ischemia (netrin-1 0.27 ± 0.06 vs. BSA 0.62 ± 0.04 mm3, p < 0.05).ConclusionOur results indicate that netrin-1 is an important molecule in regulating astrocyte activation and neuroinflammation in cerebral ischemia and provides a potential target for ischemic stroke therapy.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1291-5) contains supplementary material, which is available to authorized users.

Axon Guidance Molecules Guiding Neuroinflammation

“…Related to their neuroprotective roles, Netrins also appear to exhibit anti-inflammatory activity; a number of genetic, molecular and biochemical studies has revealed that Netrin signaling activates anti-inflammatory, or neuroprotective, signaling pathways in neurological disease models, where neuroinflammation contributes either to the onset of the disease, or a detrimental prognosis [572532]. In primary cultured human endothelial cells, Netrin expression is upregulated by stimulation with TNF-α and IFN-γ [4].…”

“…These results suggest that Netrin signaling is activated by pro-inflammatory stimulation, and therefore that Netrin may be involved in cellular reactions triggered by neuroinflammation [7]. Similarly, treatment with recombinant Netrin-1 can achieve anti-inflammatory responses through activation of the microglial UNC5B/PPARγ/NF-κB signaling pathway [5], and astrocytic p-AKT and PPARγ activation through the same UNC5B receptor [32].…”

Analysis of Antiapoptosis Effect of Netrin-1 on Ischemic Stroke and Its Molecular Mechanism under Deleted in Colon Cancer/Extracellular Signal-Regulated Kinase Signaling Pathway

“…In severe cases, there may even be hemiplegia, hemianopia, aphasia, sensory disturbance, and disturbance of consciousness, and in severe cases, it threatens the lives [ 5 ]. Clinical observations have found that a variety of signal pathways may be activated when the ischemic stroke occurs, causing different degrees of damage to the brain tissue and then leading to neuronal cell apoptosis [ 6 ]. Therefore, the key point for the treatment of ischemic stroke is the protection of neurons in the ischemic environment.…”

Microglia polarization in heat-induced early neural injury

“…In the central nervous system diseases such as Parkinson's disease, Alzheimer's disease, atrophic lateral sclerosis, multiple sclerosis, and stroke, microglia can rapidly develop an early inflammatory reaction, followed by astrocyte reaction [17][18][19][20].…”