Age-Dependent Determinants of Blood-Derived Monocytes Influence Neuroinflammatory Milieu at the TBI Injury Site

Abstract

Traumatic brain injury is a leading cause of neurologic injury. Excess and prolonged neuroinflammation post-injury negatively influences recovery outcomes. Blood-derived monocytes are capable of performing efferocytosis, the immunologically silent engulfment of cellular debris, which is critical for removing hazardous cellular corpses and concurrently resolving inflammation. Age-at-injury profoundly effects TBI recovery outcomes also. The phenotypic and functional plasticity of blood-derived monocytes (BDMs), as well as prior studies relating age and BDM activity, place BDMs at the crossroads these two advantageous elements, making them a promising potential therapeutic option for TBI. In this thesis, we assess how juvenile and adult BDMs differ in their response to TBI, hypothesizing that juvenile BDMs will take greater action to discourage neuroinflammation and promote tissue recovery. We performed passive injections of juvenile BDMs into CCI injured adult mice. We immunohistochemically stained the tissue for cell type and polarization state markers, then visualized the injured cortex and hippocampus with fluorescence microcopy probes and 3D reconstruction of confocal images. We quantified the lesion volume, IgG deposition and the infiltration, polarization, engulfment activity, distribution, and morphology of BDMs and resident mononuclear phagocytes during the acute phase of injury. We also looked at the population and polarization of resident mononuclear phagocytes during the chronic phase of TBI. We found an overall reduction in tissue damage in juvenile injected mice, and the injected BDMs acted in a manner that suggests the resolution of harmful inflammation after TBI.