Developmentally controlled expression of Cxcr4 by hematopoietic progenitors allows tracing of monocyte function in stroke

Monocyte-derived and tissue-resident macrophages, such as microglia, belong to independent lineages with distinct functions in steady state. During inflammation, however, changes in phenotypes and transcriptional profiles make it difficult to assess their respective roles in pathology. Here, we report that developmentally controlled expression of Cxcr4 by hematopoietic progenitors allows highly specific inducible lineage tracing of hematopoietic stem cell-derived monocytes during inflammation. In two stroke models, we found that monocytes recruited to the brain were confined to the lesion and its surrounding during the acute phase. However, monocytes did not engraft in peri-lesional tissue, but were enclosed in scar tissue by microglia and astrocytes after completed repair. Transcriptional profiles of brain monocytes and microglia reflect major differences in signaling pathways, paracrine mediators, and proliferative behavior. Initial recruitment and subsequent enclosure of monocytes required Cxcr4. Our data show that CXCR4 signaling regulates a specific monocyte-mediated contribution to injury and repair in stroke.