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

Abstract

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 in and ex vivo 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.

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

“…Although microglial depletion has been reported to reduce neuroinflammation leading to improved disease phenotype in several mouse models of neurodegenerative diseases, it has previously been shown to have detrimental effects on stroke outcome in healthy animals [19,21,31]. A study utilizing oral administration of PLX3397 to silence the CSF1R in rats prior to stroke reported that it exacerbated stroke severity and actually increased the infarct size at 3 days by increasing the production of inflammatory mediators by astrocytes (IL-1b, iNOS, IL-6).…”

“…To address these questions, we used a molecular approach to eliminate microglia. Colony-stimulating factor 1 receptor (CSF1R) signaling regulates proliferation, differentiation, and function of macrophage lineage cells, such as microglia, and is involved in the regulation of homeostatic as well as inflammatory effects of microglia [19][20][21][22]. Pharmacologic inhibition of CSF1R has been reported to be beneficial in Alzheimer's disease [21,22].…”

Microglial regulation of satiety and cognition

“…However, appetite and feeding remain largely unaffected, at least in adults. As such, the few studies that have investigated food intake or body weight after exposure to PLX compounds report them to be unchanged in chow‐fed young adult mice . Similarly, studies employing other pharmacological agents to block microglial proliferation, activity or interactions with neurones (eg AraC, mice, 15 μg μL ‐1 i.c.v.…”

“…As such, the few studies that have investigated food intake or body weight after exposure to PLX compounds report them to be unchanged in chow-fed young adult mice. 21,107,108 Similarly, studies employing other pharmacological agents to block microglial proliferation, activity or interactions with neurones (eg AraC, mice, 15 μg μL -1 i.c.v. at 0.11 μL L -1 for 4 weeks 103 ; minocycline: mice, 40 mg kg -1 in drinking water for 2 weeks 65 ; annexin-V: mice, 200 μg kg -1 i.v.…”

“…Learning-induced microglial activation may also orchestrate strategic remodelling of dendritic spines, which is essential for successful cognition. Figure (95) LPS in arcute nucleus slice preparations: mouse & rat (108) ICV TLR2 activation: mouse (97) ICV minocycline: rat (108) Cx3cr1-Dtr rats (acute conditional microglial knockout: rat (20) PLX5622 in HFD: mouse (106) Drinking water depletion minocycline: mouse (65) CSFR1 inhibition with PLX compounds: mouse (21,106,107) Ara-C (in cases of normal chow): mouse (102) Ara-C (in cases of HFD): mouse (102) Annexin-V (in cases of HFD): mouse (65) Annexin-V (in cases of normal chow): mouse (65) Minocycline: humans (112) Microglial leptin receptor depletion: mouse (110) Embroyonic microglial depletion: mouse (111) ICV visfatin: mouse (96) Obesity (males but not females): mouse & rat (98,101,104) HFD: mouse & rat (99,100,101) the basolateral amygdala, a circuit that interacts with the orexigenic networks of the PVT to establish valence in satiety-sensing. 115,116 In support of this idea, we see greater neuronal activation in the PVT in response to feeding in the absence of microglia.…”