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Repair-Associated Macrophages Increase after Early-phase Microglia Attenuation to Promote Ischemic Stroke Recovery

ABSTRACT:

Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12240 | MetaboLights | 2025-02-20

REPOSITORIES: MetaboLights

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Project description:Objective: Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. Methods: High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. Results: We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. Significance: These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention. Total RNA was isolated from three independently-generated sets of flow sorted bone marrow monocytes (CD11b+ CD45high CD115+ Ly6G- cells) and brainstem microglia (CD11b+ CD45low CD115low Ly6G- cells) for Illumina RNA-Seq, and two additional pools were subsequently generated and submitted for Affymetrix Mouse Exon 1.0ST microarray. Two of the RNA-Seq samples were additionally analyzed by the microarray, for a total of 6 samples (3 monocyte, 3 microglia) in each platform. Data outputs were analyzed by two analysis methods each (RNA-Seq data: ALEXA-Seq and Cufflinks; microarray data: Partek and Aroma). All four lists were merged into a new high-confidence gene list of transcripts that were significantly differentially expressed (DE) in three out of the four analyses. In this dataset, we includeRNA-Seq data obtained from flow sorted mouse bone marrow monocytes and brainstem microglia.

Project description:Objective: Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. Methods: High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. Results: We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. Significance: These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention. Total RNA was isolated from three independently-generated sets of flow sorted bone marrow monocytes (CD11b+ CD45high CD115+ Ly6G- cells) and brainstem microglia (CD11b+ CD45low CD115low Ly6G- cells) for Illumina RNA-Seq, and two additional pools were subsequently generated and submitted for Affymetrix Mouse Exon 1.0ST microarray. Two of the RNA-Seq samples were additionally analyzed by the microarray, for a total of 6 samples (3 monocyte, 3 microglia) in each platform. Data outputs were analyzed by two analysis methods each (RNA-Seq data: ALEXA-Seq and Cufflinks; microarray data: Partek and Aroma). All four lists were merged into a new high-confidence gene list of transcripts that were significantly differentially expressed (DE) in three out of the four analyses. In this dataset, we include exon expression data obtained from flow sorted mouse bone marrow monocytes and brainstem microglia.

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Repair-Associated Macrophages Increase after Early-phase Microglia Attenuation to Promote Ischemic Stroke Recovery

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