Abstract
Under pathological conditions in the central nervous system (CNS), including spinal cord injury, astrocytes show detrimental effects against neurons. It is also known that astrocytes sometimes exert beneficial effects, such as neuroprotection and secretion of axonal growth factors. If beneficial effects of astrocytes after injury could be induced, dysfunction of the injured CNS may improve. However, a way of promoting beneficial functions in astrocytes has not been elucidated. In the current study, we focused on neuroleukin (NLK), which is known to have axonal growth activities in neurons. Although NLK is secreted from astrocytes, the function of NLK in astrocytes is poorly understood. We aimed to clarify the mechanism of NLK secretion in astrocytes and the functional significance of secreted NLK from astrocytes. Stimulation of cultured astrocytes with recombinant NLK significantly elevated the secretion of NLK from astrocytes. Furthermore, astrocyte conditioned medium treated with NLK increased axonal density in cultured cortical neurons. Recombinant NLK itself directly increased axonal density in cultured neurons. These results indicated that NLK secreted from astrocytes acted as an axonal growth factor and that secretion was stimulated by extracellular NLK. To elucidate a direct binding molecule of NLK on astrocytes, drug affinity responsive target stability (DARTS) analysis was performed. A 78 kDa glucose regulated protein (GRP78) was identified as a receptor for NLK, which was related to the secretion of NLK from astrocytes. When NLK was injected into the lesion site of spinal cord injured mice, axonal density in the injured region was significantly increased and hindlimb motor function improved. These results suggested that NLK-GRP78 signalling was important for the beneficial effects of astrocytes. This study strengthens the potential of astrocytes for use as therapeutic targets in CNS traumatic injury.
Highlights
Astrocytes are multifunctional cells that have important roles in homeostasis of neural networks in the central nervous system (CNS)
It has been previously reported that astrocytes play beneficial roles by secreting axonal growth factors (Teshigawara et al, 2013; Shih et al, 2014)
Little is known about how astrocytes are activated to secrete the axonal growth factors
Summary
Astrocytes are multifunctional cells that have important roles in homeostasis of neural networks in the central nervous system (CNS). Under pathological conditions in the CNS, such as traumatic injury of the brain and spinal cord, astrocytes exert both detrimental and beneficial effects on neural networks (Karimi-Abdolrezaee and Billakanti, 2012; Karve et al, 2016), including neurotoxic effects after injury (Liddelow et al, 2017). CNS traumatic injury induces the activation of astrocytes that form glial scars surrounding the lesion site. Astrocytes are reported to express and secrete axonal growth factors such as brain-derived neurotrophic factor, nerve growth factor, and periostin in the injured spinal cord (Dougherty et al, 2000; Krenz and Weaver, 2000; Shih et al, 2014). The mechanism to increase beneficial astrocyte activity is poorly understood
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