Macrophages on the margin: choroid plexus immune responses

Abstract

The choroid plexus (ChP), an epithelial bilayer containing a network of mesenchymal, immune, and neuronal cells, forms the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While best recognized for secreting CSF, the ChP is also a hotbed of immune cell activity and can provide circulating peripheral immune cells with passage into the central nervous system (CNS). Here, we review recent studies on ChP immune cells, with a focus on the ontogeny, development, and behaviors of ChP macrophages, the principal resident immune cells of the ChP. We highlight the implications of immune cells for ChP barrier function, CSF cytokines and volume regulation, and their contribution to neurodevelopmental disorders, with possible age-specific features to be elucidated in the future.

Keywords: blood–cerebrospinal fluid barrier; border-associated macrophages; choroid plexus; neurodevelopmental psychiatric disorders; neuroimmune functions.

Figure 1.. The diverse identities and functions of choroid plexus (ChP) macrophages across development.

Past studies and recent single-cell transcriptomics analyses revealed that the ChP harbors a variety of immune cells including macrophages, basophils, mast cells, dendritic cells, monocytes, neutrophils, and lymphocytes (top, center). For T cell activities at the ChP, we refer the readers to earlier reviews [7,9] Studies in mice showed that already during early brain development, ChP macrophages reside at two distinct anatomical positions—on the apical surface (epiplexus) and in the stromal space. In vivo live imaging of fluorescence-labeled macrophages (e.g., Cx₃cr₁^GFP/+; top, left and top, right) using two-photon microscopy paired with computational algorithms has revealed diverse behaviors of ChP macrophages [27,28]. During development (bottom, left), macrophages are round with short, stunted processes. They survey the surroundings and can enter the CSF via distal tips of ChP villi following inflammatory triggers. In mature ChP (bottom, right), macrophages have long, ramified processes. In addition to routine surveillance, mature macrophages can actively take up blood-borne substances including fluorescent dextrans. Stromal macrophages elongate in the periluminal region, as if coating the blood vessels, during LPS-induced systemic inflammation, while epiplexus macrophages immediately rush to laser-induced focal injury sites on the ChP. aCSF: artificial CSF; T1, T2 and T3: indicate different timeframes to demonstrate the processes are motile over time.