Identification and Characterization of CD38+ Engulfing Periarterial Brain Border Macrophages

Abstract

Elimination of waste material in the central nervous system (CNS) plays a crucial role in maintaining an optimal environment for neuronal activity. Advances in the characterization of the glymphatic system and of border-associated macrophages (BAMs) have elucidated independent mechanisms for CNS clearance, although the presence of collaborative activity between the two processes is unclear. We set out to characterize the interaction of BAMs with draining material and observed antigen-laden BAMs exclusively localized to periarterial spaces in the mouse cortex, which also serves as the site of glymphatic influx. We then characterized engulfing perivascular BAMs (PVM) using single-cell RNA sequencing data and flow cytometry, identifying a CD38+ PVM population with enriched gene signature for multiple components of the endocytic pathway in steady-state conditions and subsequently visualizing its presence along periarterial pathways. These data suggest the hypothesis that CD38+ perivascular macrophages along periarterial spaces are able to selectively engulf material due (at least in part) to their enriched endocytic capability. Given the pathological role of protein aggregates and other antigens in a number of neurodegenerative disorders, identification and detailed characterization of engulfing PVMs in homeostatic and disease conditions present a promising avenue for future therapeutic development.