Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Neurosci. 2020 Mar;23(3):351-362. doi: 10.1038/s41593-020-0585-y. Epub 2020 Feb 10.
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.
单核细胞衍生的和组织驻留的巨噬细胞是先天免疫系统中具有不同发生起源的组成部分。评估它们在病理学中的各自功能很复杂，因为在炎症过程中巨噬细胞表型会发生变化。在这里，我们发现 Cxcr4-CreER 可实现造血干细胞（HSC）的永久性遗传标记，并区分 HSC 衍生的单核细胞与小神经胶质细胞和其他组织驻留的巨噬细胞。通过将 Cxcr4-CreER 介导的谱系追踪与光血栓性中风中的 Cxcr4 抑制或条件性 Cxcr4 消融相结合，我们发现 Cxcr4 促进初始单核细胞浸润，并随后将单核细胞衍生的巨噬细胞限制在梗死组织内。短暂局灶性缺血后，Cxcr4 缺陷会减少单核细胞浸润，并使单核细胞衍生的巨噬细胞中模式识别和防御反应基因的表达减弱。这与小胶质细胞反应改变和预后恶化有关。因此，Cxcr4 是脑缺血后先天免疫系统介导的防御反应所必需的。我们进一步提出 Cxcr4-CreER 作为研究 HSC 衍生细胞功能的通用工具。
