1. Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke
- Author
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Kathrin Klee, Dagmar Schütz, Praveen Ashok Kumar, Thomas Ulas, Christoph Redecker, Friederike Saaber, Yves Werner, Frederic Geissmann, Amelie Lupp, Elvira Mass, Joachim L. Schultze, Kristian Händler, Ralf Stumm, and Arik Horne
- Subjects
immunology [Brain Ischemia] ,0301 basic medicine ,CXCR4 protein, mouse ,pathology [Ischemic Attack, Transient] ,CXCR4 ,Monocytes ,Brain Ischemia ,0302 clinical medicine ,immunology [Ischemic Attack, Transient] ,Mice, Knockout ,Microglia ,General Neuroscience ,pathology [Microglia] ,Cerebral Infarction ,immunology [Microglia] ,Cell biology ,Stroke ,Haematopoiesis ,Treatment Outcome ,medicine.anatomical_structure ,Ischemic Attack, Transient ,medicine.symptom ,Stem cell ,immunology [Cerebral Infarction] ,Receptors, CXCR4 ,pathology [Hematopoietic Stem Cells] ,Inflammation ,Biology ,pathology [Brain Ischemia] ,Article ,immunology [Monocytes] ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Cell Lineage ,ddc:610 ,immunology [Hematopoietic Stem Cells] ,immunology [Receptors, CXCR4] ,Innate immune system ,pathology [Monocytes] ,Monocyte ,Thrombosis ,Hematopoietic Stem Cells ,Immunity, Innate ,genetics [Receptors, CXCR4] ,pathology [Thrombosis] ,pathology [Cerebral Infarction] ,genetics [Immunity, Innate] ,Mice, Inbred C57BL ,030104 developmental biology ,pathology [Stroke] ,metabolism [Receptors, CXCR4] ,Neuroscience ,immunology [Stroke] ,030217 neurology & neurosurgery - 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.
- Published
- 2020
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