Transcriptome-based profiling reveals a macrophage pedigree and identifies Irf8 as pivotal for macrophage homeostasis and function

Recent studies have shown that tissue macrophages (MF) arise from embryonic progenitors of the yolk sac (YS) and fetal liver and colonize the tissues before birth. Further studies have proposed that developmentally distinct tissue MF can be identified based on the differential expression of F4/80 and CD11b, but whether a characteristic transcriptional profile exists is largely unknown. Here, we established an inducible fate mapping system that facilitated the identification of A2 progenitors of the YS as source of F4/80hi but not CD11bhi MF. Large-scale transcriptional profiling of MF precursors from the YS until adulthood allowed the description of a complex MF pedigree. We further identified a distinct molecular signature of F4/80hi and CD11bhi MF and found that Irf8 was vital for MF maturation and the innate immune response. Our data provide new cellular and molecular insights into the origin and developmental pathways of tissue MF.

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Hagemeyer N, Kierdorf K, Frenzel K, Xue J, Ringelhan M, Abdullah Z, Godin I, Wieghofer P, Costa Jordão MJ, Ulas T, Yorgancioglu G, Rosenbauer F, Knolle PA, Heikenwalder M, Schultze JL, Prinz M