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Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain
C Siret1, M van Lessen2, J Bavais1,3
1Aix-Marseille Univ, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, France.
Abstract:
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 Cx3cr1GFP x Cx3cr1-Cre;RosatdT reporter mice for finer mapping of the lineages, we establish that CD45lowCX3CR1- pvMs are derived from CX3CR1+ precursors and require PU.1 during their ontogeny. In parallel, results from the Cxcr4-CreErt2;Rosa26tdT 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 CD45low and CX3CR1- pvM population.
Insights
Researchers discovered a new type of perivascular macrophage (pvM) in the brain. This CX3CR1-negative pvM population is distinct from previously known types and plays a role in brain immune regulation.
Area of Science:
- Neuroimmunology
- Cerebrovascular Biology
- Macrophage Biology
Background:
- Perivascular macrophages (pvMs) are crucial immune cells residing near brain blood vessels, involved in brain drainage and immune responses.
- Existing knowledge primarily describes a homogenous population of pvMs, characterized by specific surface markers.
Purpose of the Study:
- To investigate the heterogeneity of perivascular macrophage populations within the adult mouse brain.
- To characterize novel pvM subsets and their developmental origins and functions.
Main Methods:
- Utilized reporter mouse models (Cx3cr1GFP, Cx3cr1-Cre;Rosa tdT, Cxcr4-CreErt2;Rosa26 tdT).
- Employed whole brain and section immunofluorescence, flow cytometry, and single-cell RNA sequencing.
- Analyzed pvM populations following photothrombotic stroke induction.
Main Results:
- Identified a novel CX3CR1-negative perivascular macrophage population alongside the known Lyve1+F4/80+CD206+CX3CR1+ pvMs.
- Characterized a parenchymal pvM subset (Lyve1+MHCII-CD45low).
- Established that CD45lowCX3CR1- pvMs originate from CX3CR1+ precursors and demonstrated bone marrow-independent replenishment of Lyve1+ pvMs.
Conclusions:
- The parenchymal perivascular macrophage population is more heterogeneous than previously understood.
- A distinct CD45low and CX3CR1- pvM subset exists within the brain parenchyma.
- Perivascular macrophages show increased numbers following ischemic stroke.
