Tissue-resident macrophages are phagocytic cells that are essential for the response to injury and infection. Both within and between tissues, macrophages can show distinct characteristics, but are these attributes developmentally defined or determined by the microenvironment? In the mouse lung, there are two distinct macrophage populations: alveolar macrophages that reside within the lumen of the alveoli and interstitial macrophages that occupy the interalveolar space and elsewhere in the lung parenchyma. Some studies have suggested that alveolar macrophages originate from and are repopulated by an interstitial macrophage precursor, while others indicated that they can maintain themselves independently. Serena Tan and Mark Krasnow (p. ) now show that there are in fact three developmentally distinct lineages that populate the lung in three waves, with minimal interconversion between them – at least under homeostatic conditions. The first population, derived from yolk sac haematopoietic cells, populate the interstitial space in embryogenesis, but become confined to peripheral and perivascular regions postnatally. The second, of as-yet-unknown origin, initially occupy the interstitium but then become alveolar macrophages. The third population enters the lung postnatally from circulating monocytes and constitute the majority of mature adult interstitial macrophages. In the lung at least, it appears that developmental origin, rather than environmental influence, is the primary determinant of macrophage identity and diversity.
