Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke.
Animals
Brain Ischemia
/ immunology
Cell Lineage
Cerebral Infarction
/ immunology
Hematopoietic Stem Cells
/ immunology
Immunity, Innate
/ genetics
Ischemic Attack, Transient
/ immunology
Mice, Inbred C57BL
Mice, Knockout
Microglia
/ immunology
Monocytes
/ immunology
Receptors, CXCR4
/ genetics
Stroke
/ immunology
Thrombosis
/ pathology
Treatment Outcome
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
24
09
2018
accepted:
02
01
2020
pubmed:
12
2
2020
medline:
14
4
2020
entrez:
12
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32042176
doi: 10.1038/s41593-020-0585-y
pii: 10.1038/s41593-020-0585-y
pmc: PMC7523735
mid: NIHMS1622479
doi:
Substances chimiques
CXCR4 protein, mouse
0
Receptors, CXCR4
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
351-362Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130345
Pays : United States
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