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Modulation of macrophage and microglial responses to axonal injury in the peripheral and central nervous systems
D A Lazar1, D B Ellegala, A M Avellino
1Department of Neurological Surgery, University of Washington, Puget Sound Veterans Affairs Health Care System, Seattle 98195-6570, USA.
Objective:
After axonal injury, macrophages rapidly infiltrate and become activated in the mammalian peripheral nervous system (PNS) but not the central nervous system (CNS). We used the dorsal root pathway to study factors that modulate the response of macrophages to degenerating axons in both the PNS and the CNS.
Methods:
Lewis rats underwent transection of dorsal roots (Group 1), stab within the spinal cord (Group II), crush at the dorsal root entry zone (Group III), transection of dorsal roots combined with a CNS lesion (Group IV), or systemic administration of a known activator of macrophages, lipopolysaccharide, alone (Group V) or combined with transection of dorsal roots (Group VI). ED-1 antibody stained for macrophages and activated microglia at 7, 14, and 42 days postinjury.
Results:
At early time points, Group I demonstrated ED-1 cells in the PNS but not the CNS portion of the degenerating dorsal roots. Group II revealed ED-1 cells near the stab lesion. Group III demonstrated ED-1 cells adjacent to the dorsal root entry zone crush site. Group IV revealed ED-1 cells along both the PNS and the CNS portions of the degenerating dorsal roots when the CNS lesion was placed near the transected roots. Group V demonstrated few ED-1 cells in the PNS and the CNS, whereas Group VI revealed a marked ED-1 cellular response along both the PNS and the CNS portions of the transected dorsal roots.
Conclusion:
Local CNS trauma and systemic administration of lipopolysaccharide can "prime" macrophages/microglia, resulting in an enhanced response to degenerating axons in the CNS. Such priming might prove useful in promoting axonal regeneration.
Insights
Macrophages respond to nerve injury in the peripheral nervous system (PNS) but not the central nervous system (CNS). Local CNS trauma or systemic lipopolysaccharide can prime macrophages for CNS axonal injury response.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Macrophages infiltrate and activate after axonal injury in the peripheral nervous system (PNS).
- Macrophages typically do not infiltrate or activate in response to axonal injury within the central nervous system (CNS).
Purpose of the Study:
- To investigate factors modulating macrophage response to degenerating axons in both PNS and CNS.
- To understand differential macrophage activation between PNS and CNS following axonal injury.
Main Methods:
- Lewis rats underwent various dorsal root and CNS injury models.
- Systemic administration of lipopolysaccharide (LPS), a macrophage activator, was used.
- Immunohistochemistry with ED-1 antibody identified macrophages and activated microglia at multiple time points post-injury.
Main Results:
- Macrophages were observed in the PNS but not CNS after dorsal root transection.
- Local CNS trauma or systemic LPS administration led to macrophage infiltration in the CNS.
- Combined PNS and CNS injury, or LPS with PNS injury, resulted in significant macrophage/microglia response in both compartments.
Conclusions:
- Local CNS trauma and systemic lipopolysaccharide can prime CNS macrophages/microglia.
- Primed macrophages exhibit an enhanced response to degenerating axons within the CNS.
- This priming effect may hold potential for promoting axonal regeneration in the CNS.