Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain

• Published in: Nature communications Vol. 13; no. 1; pp. 7366 - 14
• Main Authors: Siret, C., van Lessen, M., Bavais, J., Jeong, H. W., Reddy Samawar, S. K., Kapupara, K., Wang, S., Simic, M., de Fabritus, L., Tchoghandjian, A., Fallet, M., Huang, H., Sarrazin, S., Sieweke, M. H., Stumm, R., Sorokin, L., Adams, R. H., Schulte-Merker, S., Kiefer, F., van de Pavert, S. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/1; 14/19; 14/63; 38/91; 631/250/1617/2069; 631/250/2502; 631/250/2504/342; 631/378/371; 64; 64/60; Animal models; Animals; Bone marrow; Brain; CD45 antigen; CX3CR1 protein; CXCR4 protein; Flow Cytometry; Gene sequencing; Heterogeneity; Humanities and Social Sciences; Immunofluorescence; Immunoregulation; Leukocyte Count; Life Sciences; Macrophages; Mapping; Mice; multidisciplinary; Ontogeny; Parenchyma; Phagocytes; PU.1 protein; Replenishment; Rodents; Science; Science (multidisciplinary); Three dimensional flow; Wound drainage
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35166-9

Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain and section immunofluorescence, flow cytometry, and single cell RNA sequencing, besides the Lyve1 + F4/80 + CD206 + CX3CR1 + pvMs, we identify a CX3CR1 – pvM population that shares phagocytic functions and location. Furthermore, the brain parenchyma vasculature mostly hosts Lyve1 + MHCII – pvMs with low to intermediate CD45 expression. Using the double Cx3cr1 GFP x Cx3cr1-Cre ; Rosa tdT reporter mice for finer mapping of the lineages, we establish that CD45 low CX3CR1 – pvMs are derived from CX3CR1 + precursors and require PU.1 during their ontogeny. In parallel, results from the Cxcr4-CreErt2 ; Rosa26 tdT lineage tracing model support a bone marrow-independent replenishment of all Lyve1 + pvMs in the adult mouse brain. Lastly, flow cytometry and 3D immunofluorescence analysis uncover increased percentage of pvMs following photothrombotic induced stroke. Our results thus show that the parenchymal pvM population is more heterogenous than previously described, and includes a CD45 low and CX3CR1 – pvM population. Perivascular macrophages (pvMs) are important for brain drainage and immune regulation. Here the authors analyse various reporter mouse strains for finer mapping of pvM subsets and lineage differentiation, and propose CX3CR1negative and CD45low as additional markers of intermediate pvMs for studying this heterogenous population.