Acta Neuropathologica

, Volume 135, Issue 4, pp 551–568 | Cite as

Distinguishing features of microglia- and monocyte-derived macrophages after stroke

  • Golo Kronenberg
  • Ria Uhlemann
  • Nadine Richter
  • Friederike Klempin
  • Stephanie Wegner
  • Lilian Staerck
  • Susanne Wolf
  • Wolfgang Uckert
  • Helmut Kettenmann
  • Matthias Endres
  • Karen Gertz
Original Paper

Abstract

After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were further collated with oligodendrocyte, astrocyte, and neuron transcriptomes, resulting in a dataset of microglia- and monocyte-specific genes in the ischemic brain. Functional categories significantly enriched in monocytes included migration, proliferation, and calcium signaling, indicative of strong activation. Whole-cell patch-clamp analysis further confirmed this highly activated state by demonstrating delayed outward K+ currents selectively in invading cells. Although both cell types displayed a mixture of known phenotypes pointing to the significance of ‘intermediate states’ in vivo, blood-derived macrophages were generally more skewed toward an M2 neuroprotective phenotype. Finally, we found that decreased engraftment of blood-borne cells in the ischemic brain of chimeras reconstituted with BM from Selplg−/− mice resulted in increased lesions at 7 days and worse post-stroke sensorimotor performance. In aggregate, our study establishes crucial differences in activation state between resident microglia and invading macrophages after stroke and identifies unique genomic signatures for either cell type.

Keywords

Cerebral ischemia Bone-marrow chimera Microglia Macrophage Middle cerebral artery occlusion 

Notes

Acknowledgements

The technical assistance of Bettina Herrmann, Melanie Kroh, and Stefanie Balz is gratefully acknowledged. We also thank the Charité Core Facility ‘7T Experimental MRIs’ and the Deutsches Rheuma-Forschungszentrum Berlin ‘Flow Cytometry Core Facility’ (FCCF) for excellent support.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

401_2017_1795_MOESM1_ESM.xlsx (107 kb)
Genes upregulated in blood-derived macrophages as compared to resident microglia (DsRed>EGFP) (XLSX 106 kb)
401_2017_1795_MOESM2_ESM.xlsx (185 kb)
Genes upregulated in resident microglia as compared to blood-derived macrophages (EGFP>DsRed) (XLSX 185 kb)
401_2017_1795_MOESM3_ESM.xls (1.2 mb)
Annotation enrichment analysis for the dataset DsRed>EGFP (XLS 1224 kb)
401_2017_1795_MOESM4_ESM.xls (1002 kb)
Annotation enrichment analysis for the dataset EGFP>DsRed (XLS 1001 kb)
401_2017_1795_MOESM5_ESM.xlsx (39 kb)
Genes selectively upregulated in blood-derived macrophages (XLSX 38 kb)
401_2017_1795_MOESM6_ESM.xlsx (65 kb)
Genes selectively upregulated in microglia (XLSX 64 kb)
401_2017_1795_MOESM7_ESM.xlsx (591 kb)
Comparison of previously described microglia-specific genes [7] with our dataset EGFP>DsRed. The first sheet of the Exel file represents a comparison of our candidate genes with the dataset published by Butovsky and co-workers [7]. Note that 56 transcripts occur in both datasets. The second sheet of the Exel file contains the transcripts specifically expressed in microglia (EGFP>DsRed) but not described by Butovsky and co-workers. Finally, the third sheet is identical to the second sheet except for the fact that all transcripts of unknown function were removed (XLSX 590 kb)
401_2017_1795_MOESM8_ESM.xlsx (12 kb)
Comparison of previously described microglia-enriched transcripts in EAE [7] to our dataset EGFP>DsRed (XLSX 12 kb)
401_2017_1795_MOESM9_ESM.pdf (402 kb)
Flow cytometry of blood from WTDsRed → MacGreen BM chimeras. a Gating strategy. b Percentages (frequency of parent) of DsRed+ cells in granulocytes, monocytes, and lymphocytes. On average, 20.9% of blood monocytes express the fluorophore DsRed. N=31 mice. c Gating strategy for post-stroke analysis of white blood cells.Flow cytometry of CD11b pre-enriched brain cells post stroke. d Gating strategy. Infiltrating DsRed+ cells did not express CD3, Cd335 and Ly6G. N=7 WTDsRed → MacGreen BM chimeras (PDF 402 kb)
401_2017_1795_MOESM10_ESM.pdf (139 kb)
Transcriptomic analysis of CD11b+ DsRed+ CD45hi cells harvested from the ischemic brain of Selplg-KODsRed → WT chimeras and Selplg-WTDsRed → WT chimeras at 7 days after MCAo/reperfusion. The detailed protocol is accessible at GEO, GSE105011. a FACS gating strategy. b Hierarchical clustering did not reveal a distinction in the transcriptional response of cells derived from Selplg-WT and Selplg-KO BM. c Interexperiment correlation analysis. d Comparison of key M1 and M2 transcripts (PDF 139 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Golo Kronenberg
    • 1
    • 2
    • 3
  • Ria Uhlemann
    • 1
  • Nadine Richter
    • 4
  • Friederike Klempin
    • 1
    • 2
    • 4
  • Stephanie Wegner
    • 1
  • Lilian Staerck
    • 4
  • Susanne Wolf
    • 4
  • Wolfgang Uckert
    • 4
    • 5
  • Helmut Kettenmann
    • 4
  • Matthias Endres
    • 1
    • 6
  • Karen Gertz
    • 1
  1. 1.Center for Stroke Research, Klinik für Neurologie, and Department of Experimental NeurologyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  2. 2.Klinik für Psychiatrie und Psychotherapie, Campus MitteCharité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  3. 3.Klinik und Poliklinik für Psychiatrie und Psychotherapie, Zentrum für NervenheilkundeUniversitätsmedizin RostockRostockGermany
  4. 4.Max-Delbruck-Center for Molecular Medicine (MDC) in the Helmholtz AssociationBerlinGermany
  5. 5.Institut für BiologieHumboldt-Universität BerlinBerlinGermany
  6. 6.DZNE (German Center for Neurodegenerative Diseases)BerlinGermany

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