Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Abstract

Chronic neuroinflammation with sustained microglial activation occurs following moderate-to-severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this translational study, we examined the effects of delayed depletion and subsequent repopulation of microglia on chronic neurodegeneration and functional recovery up to three months posttrauma. A CSF1R inhibitor, PLX5622, was administered to injured adult male C57Bl/6 mice at one month after controlled cortical impact to remove chronically activated microglia, and the inihibitor was withdrawn 1 week later to allow microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology, similar to that of sham control uninjured animals, whereas microglia in untreated injured animals showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBIassociated neuropathological changes at 3 months posttrauma; these included a smaller cortical lesion, reduced neuronal cell death in the injured cortex and ipsilateral hippocampus, and decreased NOX2-dependent reactive microgliosis. Furthermore, delayed depletion of microglia led to widespread changes in the cortical transcriptome, including alterations in gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity.PLX5622 treated animals showed significantly improved neurological recovery using a variety of complementary neurobehavioral evaluations.These included beam walk and rotorod tests for sensori-motor function, as well as Ymaze, novel object recognition, and Morris water maze tests to evaluate cognitive function. Together, our findings show that chronic phase removal of neurotoxic microglia using CSF1R inhibitors after experimental TBI can markedly reduce chronic neuroinflammation and neurodegeneration, as well as related long-term motor and cognitive deficits. Thus, CSF1R inhibition may provide a clinically feasible approach to limit posttraumatic neurodegeneration and neurological dysfunction following head injury.with neurobehavioral assessment and histology. Rodney M. Ritzel contributed with experimental design, collected and performed data analysis of flow cytometry; James P. Barrett contributed to data collection and PCR analysis; Sarah J. Doran contributed to data collection and IHC analysis; Yun Jiao performed nanostring data analysis; Jennie B. Leach contributed to nanostring data analysis; Gregory L. Szeto contributed to nanostring data analysis and manuscript preparation; Bogdan A. Stoica contributed with experimental design; Alan I. Faden contributed with manuscript preparation; David J. Loane contributed to study conception and design, and manuscript preparation. All authors read and approved the manuscript prior to submission.

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

“…Neuroinflammation and gliosis can often persist for months or even years post-brain trauma 7 , 9 , and interventions aimed at attenuating this neuroinflammation have proven successful in modulating cognitive outcomes 61 , 62 . Yet, the physiological processes involved in the prolonged inflammatory state of the TBI brain remain poorly defined.…”

Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer’s Disease mice

“…To specifically ablate microglia cells in the brain we used the small molecule compound PLX5622, that is a potent inhibitor of the colony-stimulating factor 1 receptor (CSF1R) [ 50 ]. CSF1R inhibitors are widely used to study the role of microglia in several diseases [ 51 – 53 ] including neurodegenerative disease as AD [ 31 , 32 , 50 , 54 ], and we and others previously showed that four weeks of treatment with the CSF1R inhibitor PLX5622 depleted microglia in WT and APP-PS1 mice [ 31 , 32 , 35 ]. In this previous experiment, we had treated APP-PS1 and WT mice with either control or PLX5622 chow for a total of 28 days (Fig.…”

The role of innate immunity in Alzheimer's disease

“…149,150 However, injury models, such as traumatic brain injury (TBI), can cause BBB breakdown and subsequent infiltration of immune cells into the brain. 151,152 Likewise, AD pathology is also thought to propagate the loss of BBB integrity. 153 Microglial depletion and repopulation after TBI has been reported to replace chronically activated microglia with resting-state myeloid cells, resulting in decreased neuroinflammation and neuronal loss.…”

“…153 Microglial depletion and repopulation after TBI has been reported to replace chronically activated microglia with resting-state myeloid cells, resulting in decreased neuroinflammation and neuronal loss. 151 The neuroprotection conferred by the repopulated myeloid cells post-TBI relies on their induction of IL-6 trans-signaling to enhance learning and memory. 154 Therefore 156 What underlies the discrepancies between these two studies remains to be fully resolved.…”