• Of the 30 000 genes, there are ;0.1% genes whose expression is linked to the origin of the cell rather than the environment.• Marco was most conserved by embryonic origin and not altered by the environment, whereas C1qb and Plbd1 were most conserved by adult origin.Alveolar macrophages (AMs) reside on the luminal surfaces of the airways and alveoli where they maintain host defense and promote alveolar homeostasis by ingesting inhaled particulates and regulating inflammatory responses. Recent studies have demonstrated that AMs populate the lungs during embryogenesis and self-renew throughout life with minimal replacement by circulating monocytes, except under extreme conditions of depletion or radiation injury. Here we demonstrate that on a global scale, environment appears to dictate AM development and function. Indeed, transcriptome analysis of embryonic host-derived and postnatal donor-derived AMs coexisting within the same mouse demonstrated >98% correlation and overall functional analyses were similar. However, we also identified several genes whose expression was dictated by origin rather than environment. The most differentially expressed gene not altered by environment was Marco, a gene recently demonstrated to have enhancer activity in embryonic-derived but not postnatal-derived tissue macrophages. Overall, we show that under homeostatic conditions, the environment largely dictates the programming and function of AMs, whereas the expression of a small number of genes remains linked to the origin of the cell. (Blood. 2015;126(11):1357-1366 Introduction Alveolar macrophages (AMs) reside on the luminal surfaces of the airways and airspaces where they serve critical roles in host defense and alveolar homeostasis, ingesting particulates and microbes that are constantly encountered in the lungs. Importantly, under most circumstances the phagocytosis of inhaled foreign agents is silent, such that inflammatory responses are activated only under circumstances when host defenses become overwhelmed.1 Indeed, compared with macrophages from other sites, AMs are relatively ineffective at initiating immune responses.2,3 Furthermore, compared with other tissue macrophages, they display a unique repertoire of cell surface molecules and have a distinct transcriptome profile. [4][5][6] AMs are now known to derive primarily from fetal liver monocytes and self-renew throughout life with minimal replenishment from circulating monocytes. [7][8][9][10][11][12][13][14][15] This self-renewal is not only maintained under steady-state conditions, but also during acute and chronic inflammation.16 These concepts were illustrated in lung-protected bone marrow (BM) chimera studies in which lead shields were used to protect AMs during radiation. Eight weeks after BM transplantation, the lungs of these chimeras contained AMs of host origin, whereas circulating monocytes were donor-derived. 16 In these chimeric mice, we showed that during inflammation (lipopolysaccharide or influenza A infection), BM donor-derived monocytes were rapidly...