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Published on: March 30, 2018
ProBDNF inhibits infiltration of ED1+ macrophages after spinal cord injury
Ira Wong1, Hong Liao, Xianshu Bai
1Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia.
Abstract:
The central nervous system (CNS) does not regenerate partly due to the slow clearance of debris from the degenerated myelin sheath by Wallerian degeneration. The mechanism underlying the inefficiency in myelin clearance is not clear. Here we showed that endogenous proBDNF may inhibit the infiltration of ED1+ inflammatory cells after spinal cord injury. After injury, proBDNF and its receptors sortilin and p75NTR are expressed in the spinal cord as determined by Western blots and immunocytochemistry. ProBDNF and mature BDNF were released from macrophages in vitro. Macrophages in vivo (ED1+) and isolated in vitro (CD11b+) express moderate levels of proBDNF, sortilin and p75NTR. ProBDNF suppressed the migration of isolated macrophages in vitro and the antibody to proBDNF enhanced the migration. Suppression of proBDNF in vivo by administering the antiserum to the prodomain of BDNF after spinal cord injury (SCI) increased the infiltration of macrophages and increased number of neurons in the injured cord. BBB tests showed that the treatment of the antibody to proBDNF improved the functional recovery after spinal cord injury. Our data suggest that proBDNF is a suppressing factor for macrophage migration and infiltration and may play a detrimental role after SCI.
Insights
Pro-brain-derived neurotrophic factor (proBDNF) hinders macrophage infiltration after spinal cord injury. Blocking proBDNF enhances immune cell migration and improves functional recovery, suggesting a detrimental role in CNS injury.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Central nervous system (CNS) regeneration is limited by slow myelin debris clearance after injury.
- The precise mechanisms controlling this inefficient clearance remain unclear.
Purpose of the Study:
- To investigate the role of endogenous pro-brain-derived neurotrophic factor (proBDNF) in regulating inflammatory cell infiltration following spinal cord injury (SCI).
- To determine if proBDNF influences macrophage migration and impacts functional recovery after SCI.
Main Methods:
- Western blots and immunocytochemistry to detect proBDNF and its receptors (sortilin, p75NTR) post-SCI.
- In vitro studies assessing macrophage migration in response to proBDNF and anti-proBDNF antibodies.
- In vivo administration of anti-proBDNF antiserum after SCI in a mouse model.
- Behavioral assessment using BBB (Basso, Beattie, Bresnahan) tests for functional recovery.
Main Results:
- ProBDNF and its receptors (sortilin, p75NTR) were expressed in the spinal cord after injury.
- Macrophages (ED1+ in vivo, CD11b+ in vitro) expressed proBDNF, sortilin, and p75NTR.
- ProBDNF suppressed macrophage migration in vitro; anti-proBDNF antibody enhanced it.
- In vivo administration of anti-proBDNF antibody increased macrophage infiltration and neuron survival.
- Functional recovery, assessed by BBB tests, was improved following anti-proBDNF treatment.
Conclusions:
- Endogenous proBDNF acts as a suppressor of macrophage migration and infiltration into the injured spinal cord.
- Targeting proBDNF with antibodies may represent a therapeutic strategy to enhance immune cell infiltration and promote functional recovery after SCI.
- ProBDNF appears to play a detrimental role in the context of spinal cord injury and myelin debris clearance.
