CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier

• Published in: The Journal of experimental medicine 2024-02, Vol.221 (2)
• Main Authors: Lund, Harald, Hunt, Matthew A, Kurtović, Zerina, Sandor, Katalin, Kägy, Paul B, Fereydouni, Noah, Julien, Anais, Göritz, Christian, Vazquez-Liebanas, Elisa, Andaloussi Mäe, Maarja, Jurczak, Alexandra, Han, Jinming, Zhu, Keying, Harris, Robert A, Lampa, Jon, Graversen, Jonas Heilskov, Etzerodt, Anders, Haglund, Lisbet, Yaksh, Tony L, Svensson, Camilla I
• Format: Article
• Language: English
• Subjects: Cardiovascular Biology; Endothelial Cells; Ganglia, Spinal; Humans; Immunologi inom det medicinska området; Innate immunity and inflammation; Macrophages; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinska och farmaceutiska grundvetenskaper; Neuroinflammation; Neurovetenskaper; Pericytes; Permeability
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20230675

In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163+ macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.