Abstract
BackgroundSpinal cord injury (SCI) causes loss of neurons and axons and results in motor and sensory function impairments. SCI elicits an inflammatory response and induces the infiltration of immune cells, predominantly macrophages, to the injured site. Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor superfamily member (TNFRSF)-6B, is a pleiotropic immunomodulator capable of inducing macrophage differentiation into the M2 phenotype and enhancing angiogenesis. Because M2 macrophages are crucial for the recovery of impaired motor functions, we ask whether DcR3 is beneficial for the functional recovery of locomotion in Sprague-Dawley (SD) rats after SCI.MethodsContusion injury of the spinal cord was performed using a New York University impactor at the ninth thoracic vertebrae, followed by intrathecal injection of 15 μg recombinant protein comprising DcR3 (DcR3.Fc) in 5 μl of normal saline as the treatment, or 5 μl of normal saline as the control, into the injury epicenter. Functional recovery was evaluated using an open-field test weekly up to 6 weeks after injury. The cavity size and myelin sparing in the rostral-to-caudal region, including the epicenter of the injury, were then examined in SCI rats by histological staining. The expression of anti-inflammatory cytokines and the presence of M2 macrophages were determined by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry at 7 day after SCI. Statistical analysis was performed using a two-tailed Student’s t test.ResultsIntrathecal administration of DcR3.Fc significantly improved locomotor function and reduced secondary injury with a smaller wound cavity and increased myelin sparing at the lesion site. Compared with the control group, DcR3.Fc-treated rats had increased vascularization at the injury epicenter along with higher levels of interleukin (IL)-4 and IL-10 and lower level of IL-1β on DcR3.Fc-treated rats at day 7 after SCI. Moreover, higher levels of arginase I (Arg I) and CD206 (M2 macrophage markers) and RECA-1 (endothelial marker) were observed in the epicenter on day 7 after SCI by immunofluorescence staining.ConclusionsThese results indicated that DcR3.Fc may promote the M2 macrophage infiltration and enhanced angiogenesis at the lesion site, thus preserving a greater amount of spinal cord tissues and enhancing functional recovery after SCI.
Highlights
Spinal cord injury (SCI) causes loss of neurons and axons and results in motor and sensory function impairments
Improvement of hind limb functional recovery by Decoy receptor 3 (DcR3).Fc Because DcR3.Fc possesses anti-inflammatory activities and skews macrophage differentiation into M2 phenotypes, we asked whether administration of DcR3.Fc is beneficial to animals after spinal cord injury
We have shown that DcR3.Fc is able to downregulate the expression of pro-inflammatory cytokines (IL-1β, tumor necrosis factor alpha, and IL-6) and inducible nitric oxide synthase (iNOS) in macrophages [24]
Summary
Spinal cord injury (SCI) causes loss of neurons and axons and results in motor and sensory function impairments. SCI elicits an inflammatory response and induces the infiltration of immune cells, predominantly macrophages, to the injured site. Spinal cord injury (SCI) often causes incurable neurological dysfunction due to failure of axonal regeneration in adult mammals. An effective therapeutic reagent for severe SCI remains elusive, and the current treatment is limited to the early administration of highdose steroids and acute surgical intervention to minimize cord edema and the neuronal injuries [1]. The inflammatory response in the secondary phase after SCI is a series of complex cellular and molecular interactions, further reducing the opportunity for recovery of penumbral neurons and rendering functional recovery almost hopeless [5, 6]. SCI induces infiltration of immune cells, predominantly macrophages, to the injured sites. Modulation of macrophage activity to create a more permissive environment for tissue repair would benefit patients suffering from SCI and other neurodegeneration diseases
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
