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Nat Neurosci. 2020 Feb 10. doi: 10.1038/s41593-020-0585-y. [Epub ahead of print]

Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke.

Author information

1
Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
2
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. emass@uni-bonn.de.
3
Developmental Biology of the Immune System, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. emass@uni-bonn.de.
4
Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
5
PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany.
6
Lippe General Hospital, Department of Neurology, Lemgo, Germany.
7
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. geissmaf@mskcc.org.
8
Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany. ralf.stumm@med.uni-jena.de.

Abstract

Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes to the macrophage phenotype during inflammation. Here we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4 deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate-immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.

PMID:
32042176
DOI:
10.1038/s41593-020-0585-y

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