Trends in Neurosciences

Trends in Neurosciences

Volume 44, Issue 11, November 2021, Pages 864-875
Journal home page for Trends in Neurosciences

Review
Macrophages on the margin: choroid plexus immune responses

https://doi.org/10.1016/j.tins.2021.07.002Get rights and content

Highlights

  • The choroid plexus (ChP) provides a critical brain barrier that is also home to diverse and dynamic immune cell populations throughout life, as revealed by recent transcriptomic studies.

  • ChP macrophages represent the largest class of ChP immune cells and show heterogeneity.

  • Advances in in vivo imaging provide unobstructed views of ChP immune cells in their physiological setting in the brain’s ventricles.

  • Environmental cues and tightly knit receptor–ligand networks at the ChP govern immune cell recruitment and infiltration from the periphery into the central nervous system (CNS).

  • The relevance of immune cell trafficking and dynamics at the ChP is increasingly appreciated in the context of neurological conditions involving neuroinflammation.

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.

Section snippets

The ChP mediates neuroimmune interactions

The ChP (see Glossary) is located in each brain ventricle and forms the BCSFB. The ChP is commonly recognized as a source and regulator of the CSF [1., 2., 3., 4., 5.]. In recent years, the ChP has also become increasingly appreciated as a key part of the CNS neuroimmune network (Box 1; [6., 7., 8., 9.]). This review aims to summarize recent advances in our understanding of ChP immunity, with a focus on development. We refer the readers to several recent reviews on other aspects of ChP biology,

The origin and molecular identities of ChP macrophages

Macrophages are myeloid phagocytic cells that reside in all tissues and organs, including the ChP. Determining the developmental trajectory of macrophages is challenging because of their propensity to move and adopt different morphological and transcriptomic features during development and aging as well as in response to environmental cues. For example, bone-marrow-derived monocytes can infiltrate tissues and differentiate into macrophages [26].

Both the brain parenchyma and the ChP are seeded

Macrophage surveillance activity during homeostasis

Macrophages constantly survey their local environment via motile processes that can extend rapidly towards sites of tissue injury [46., 47., 48., 49.]. While meningeal macrophages and microglia were both visualized in vivo a number of years ago [32,48], it is only recently that ChP macrophages have been visualized in their native environment (Figure 1) [28]. Two-photon microscopy paired with an imaging cannula and fluorescent labeling of macrophages (e.g., Cx3cr1GFP/+) enabled the imaging of

ChP as a coordinator of CNS inflammatory responses

Inflammation is an important defensive response to infection or injury, but excessive or prolonged inflammation can be detrimental and is correlated with the vulnerability to a number of CNS disorders throughout life [55,56]. The ChP has been shown to be an entry site for pathogens, a checkpoint for peripheral immune cells into the CNS, and a regulator of cytokines and other signaling molecules in the CSF [8,57,58]. In light of this evidence, it is becoming increasingly clear that the ChP may

Concluding remarks

Recent technical advances in imaging and transcriptomics have begun to reveal the functional roles of ChP macrophages. Although currently there are more questions than answers (see Outstanding questions), the emerging model highlights the ChP as coordinating communication between the nervous and immune systems. In this capacity, the ChP is likely to be a key player in the etiology of neurodevelopmental and other brain disorders with inflammatory features, such as ASD and schizophrenia. We

Acknowledgments

We apologize to investigators whose work could not be referenced owing to space limitations. We thank N. Chamberlin for helpful discussions and editing of the manuscript and members of the Lehtinen laboratory for discussions and reading of the manuscript. This work was supported by William Randolph Hearst Fellowships (J.C. and H.X.), NIH T32 HL110852 (J.C.), the Simons Foundation [SFARI (award #402089) M.K.L.], NIH R01 NS088566 (M.K.L.), and the New York Stem Cell Foundation (M.K.L.). M.K.L. is

Declaration of interests

J.C. has been an employee of Dyne Therapeutics since April 26, 2021.

Glossary

Blood–brain barrier (BBB)
a barrier formed by endothelial cells, astrocytic end feet, and pericytes that restricts the passage of blood-borne factors into the brain.
Blood-cerebrospinal fluid barrier (BCSFB)
a barrier formed primarily by ChP epithelial cells that restricts the passage of blood-borne factors into the CSF.
Border-associated macrophages (BAMs)
macrophages that reside in the CNS barrier tissues, including the meninges, the ChP, and the perivascular space. They are also referred to as

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