CSF1R Inhibition Reduces Microglia Proliferation, Promotes Tissue Preservation and Improves Motor Recovery After Spinal Cord Injury

• Published in: Frontiers in cellular neuroscience Vol. 12; p. 368
• Main Authors: Gerber, Yannick Nicolas, Saint-Martin, Guillaume Patrick, Bringuier, Claire Mathilde, Bartolami, Sylvain, Goze-Bac, Christophe, Noristani, Harun Najib, Perrin, Florence Evelyne
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 16.10.2018; Frontiers; Frontiers Media S.A
• Subjects: Amyotrophic lateral sclerosis; Cell activation; colony stimulating factor 1 receptor; Colony-stimulating factor; Cytokines; Disease; Drug therapy; Gliosis; GW2580; Inflammation; Ischemia; Kinases; Life Sciences; Macrophage colony-stimulating factor; Macrophages; Magnetic resonance imaging; Microglia; Monocytes; motor recovery; Multiple sclerosis; Nervous system; Neurobiology; Neurons and Cognition; Neuroscience; Neurosciences; Preservation; reduced gliosis; reduced microglia proliferation; Regeneration; Spinal cord injuries; spinal cord injury; Thorax; Tumor necrosis factor-TNF; Vertebrae; France; spinal cord injury; GW2580; reduced microcavity; motor recovery; reduced gliosis; reduced microglia proliferation; colony stimulating factor 1 receptor; reduced microglia proliferation, spinal cord injury, colony stimulating factor 1 receptor, GW2580, motor recovery, reduced gliosis, reduced microcavity
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2018.00368

Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by activation and proliferation of resident microglia as well as infiltrating peripheral monocyte-derived macrophages. Depending on the time post-lesion, positive and detrimental influences of microglia/macrophages on axonal regeneration had been reported after SCI, raising the issue whether their modulation may represent an attractive therapeutic strategy. Colony-stimulating factor 1 (CSF1) regulates microglia/macrophages proliferation, differentiation and survival thus, pharmacological treatments using CSF1 receptor (CSF1R) inhibitors had been used to ablate microglia. We analyzed the effect of chronic (10 weeks) food diet containing GW2580 (a CSF1R inhibitor) in mice that underwent lateral spinal cord hemisection (HS) at vertebral thoracic level 9. Treatment started 4 weeks prior to SCI and continued until 6 weeks post-lesion. We first demonstrate that GW2580 treatment did not modify microglial response in non-injured spinal cords. Conversely, a strong decrease in proliferating microglia was observed following SCI. Second, we showed that GW2580 treatment improved some parameters of motor recovery in injured animals through better paw placement. Using and magnetic resonance imaging (MRI), we then established that GW2580 treatment had no effect on lesion extension and volume. However, histological analyses revealed that GW2580-treated animals had reduced gliosis and microcavity formation following SCI. In conclusion, CSF1R blockade using GW2580 specifically inhibits SCI-induced microglia/macrophages proliferation, reduces gliosis and microcavity formations and improves fine motor recovery after incomplete SCI. Preventing microglial proliferation may offer therapeutic approach to limit neuroinflammation, promote tissue preservation and motor recovery following SCI.