Inflammation of the Embryonic Choroid Plexus Barrier following Maternal Immune Activation

• Published in: Developmental cell Vol. 55; no. 5; pp. 617 - 628.e6
• Main Authors: Cui, Jin, Shipley, Frederick B., Shannon, Morgan L., Alturkistani, Osama, Dani, Neil, Webb, Mya D., Sugden, Arthur U., Andermann, Mark L., Lehtinen, Maria K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-12-2020
• Subjects: Animals; Calcium-Binding Proteins - metabolism; CCL2; Cell Proliferation; cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Chemokine CCL2 - metabolism; choroid plexus; Choroid Plexus - embryology; Choroid Plexus - immunology; cytokines; Imaging, Three-Dimensional; immune cells; Inflammation - pathology; Inflammation Mediators - metabolism; Macrophage Activation; maternal immune activation; Mice, Inbred C57BL; Microfilament Proteins - metabolism; neural development; Receptors, CCR2 - metabolism; Signal Transduction; Tight Junctions - metabolism; two-photon imaging; Up-Regulation; two-photon imaging; cerebrospinal fluid; maternal immune activation; immune cells; CCL2; cytokines; neural development; choroid plexus
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2020.09.020

The choroid plexus (ChP) regulates brain development by secreting instructive cues and providing a protective brain barrier. Here, we show that polyI:C-mediated maternal immune activation leads to an inflammatory response in the developing embryonic mouse brain that manifests as pro-inflammatory cerebrospinal fluid (CSF) and accumulation of ChP macrophages. Elevation of CSF-CCL2 was sufficient to drive ChP immune cell recruitment, activation, and proliferation. In addition, ChP macrophages abandoned their regular tiling pattern and relocated to the ChP-free margin where they breached the weakened epithelial barrier. We further found that these immune cells entered from the ChP into the brain via anatomically specialized “hotspots” at the distal tips of ChP villi. In vivo two-photon imaging demonstrated that surveillance behaviors in ChP macrophages had already emerged at this early stage of embryogenesis. Thus, the embryonic ChP forms a functional brain barrier that can mount an inflammatory response to external insults.
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•Embryonic ChP mounts inflammatory response to maternal infection•Embryonic CSF contains key biomarkers of neurodevelopmental disorders•Two-photon imaging reveals macrophage motility and mobility at embryonic ChP•CCL2 weakens ChP barrier and recruits immune cells through ChP barrier hotspots
Cui et al. find that the choroid plexus barrier propagates maternal inflammation to the embryonic brain by secreting inflammatory signals into the cerebrospinal fluid and gating macrophage entry into the brain via “hotspots,” contributing to an altered neuroimmune landscape. Two-photon imaging uncovers diverse surveillance behaviors of embryonic choroid plexus macrophages.