Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice

Abstract

Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Results: Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45 int microglia and CD45 hi myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. Conclusion: These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function.

For Better or for Worse: A Look Into Neutrophils in Traumatic Spinal Cord Injury

“…Administration of IL-1 receptor antagonist (IL-1RA) inhibits IL-1 signaling and suppresses neutrophil infiltration in the injured spinal cord (Yates et al, 2021). SCI mice treated with colony-stimulating factor 1 receptor antagonist PLX5622 have significantly reduced neutrophil infiltration in the injured spinal cord (Li et al, 2020). Additionally, deletion of MyD88, an adapter molecule of IL-1R and an intermediate protein in the activation of the NF-κB pathway, showed low expression of CXCL2 and no expression of CXCL1, resulting in low recruitment of neutrophils in mouse SCI (Gasse et al, 2007;Pineau et al, 2010).…”

The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury

“…In the hippocampus, microglia are essential for hippocampal neurogenesis and neuronal differentiation (Appel et al, 2018). Microglial depletion after SCI alleviated depression, cognitive dysfunction, and neuron death in the hippocampus (Li et al, 2020b). Yet, activated microglia during chronic inflammation secrete cytokines to induce apoptosis before phagocytizing hippocampal neurons (Ekdahl et al, 2003), inhibiting neuronal differentiation and favoring astrocytic differentiation (Diaz-Aparicio et al, 2020).…”

Functions and Mechanisms of the Voltage-Gated Proton Channel Hv1 in Brain and Spinal Cord Injury

“…This may reflect, in part, an incomplete understanding of the complex pathobiological mechanisms involved. Numerous experimental observations including ours (Faden et al, 2016;Skovira et al, 2016;Li Y. et al, 2020;Ritzel et al, 2020) indicate that persistent neuroinflammation contributes to long-term neurological functional deficits. However, no preferred current treatments specifically target neuroinflammatory mechanisms for CNS damage.…”