Depletion of Peripheral Monocytes Alters Long-Term Gene Expression in Microglia in a Murine Model of Traumatic Brain Injury.

Abstract

INTRODUCTION: Traumatic brain injury (TBI) is an underrecognized public health threat that can lead to long-term complications for its survivors. Monocytes are among the first immune cells recruited after TBI and interact with the microglia-the resident innate immune cells. Which drives the direction of the inflammatory response of the brain. Published data from our laboratory have shown that a brief course of peri-injury monocyte depletion attenuates long-term neurocognitive deficits and preserves white matter connectivity postinjury. To this end, we hypothesized that infiltrating monocytes shape the long-term transcriptional response of microglia after TBI. METHODS: Male C57BL/6 were randomly assigned to experimental groups-TBI, sham, TBI with monocyte depletion, and TBI with vehicle. Depletion was induced via intravenous injection of liposome-encapsulated clodronate versus naked liposomes 24 hours before injury and maintained by repeat injections. Behavioral phenotyping was done 30 days postinjury. Mice were euthanized, brains were harvested, and microglia were sorted via flow cytometry. Lastly, bulk RNA sequencing was conducted. RESULTS: Monocyte-depleted mice demonstrated improvement in motor coordination, contextual and associative learning, and memory. This was associated with different transcriptional profiles at acute injury. A distinct upregulation of signal transduction pathways and heat shock protein transcripts was also observed as compared with the vehicle TBI groups. CONCLUSION: These data show that a short course of peri-injury depletion of peripheral monocytes may have a neuroprotective effect after TBI. Alteration of the long-term transcriptional profile of microglia may be responsible for the observed changes in behavior. These data warrant further investigation into the possible therapeutic benefits of peri-injury immune modulation.