The choroid plexus synergizes with immune cells during neuroinflammation

  • Cell. 2024 Sep 5;187(18):4946-4963.e17. doi: 10.1016/j.cell.2024.07.002.
Huixin Xu  1 ,  Peter Lotfy  2 ,  Sivan Gelb  1 ,  Aja Pragana  1 ,  Christine Hehnly  1 ,  Lillian I J Byer  1 ,  Frederick B Shipley  3 ,  Miriam E Zawadzki  4 ,  Jin Cui  1 ,  Liwen Deng  5 ,  Milo Taylor  6 ,  Mya Webb  1 ,  Hart G W Lidov  1 ,  Mark L Andermann  7 ,  Isaac M Chiu  5 ,  Jose Ordovas-Montanes  8 ,  Maria K Lehtinen  9
Affiliations
  • 1. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 2. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
  • 4. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Harvard MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
  • 5. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 6. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard College, Harvard University, Cambridge, MA 02138, USA.
  • 7. Harvard MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 8. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
  • 9. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA; Harvard MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: [email protected].
PMID: 39089253 DOI: 10.1016/j.cell.2024.07.002
Abstract

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of Lipopolysaccharides (LPS) to model Meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, Macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.

Keywords
adhesion molecules; bacterial infection; blood-CSF barrier; choroid plexus; colony-stimulating factor 1; epiplexus macrophages; epithelial cells; immune recruitment; neuroinflammation.