A consistent macrophage signature characterizes macrophages of different species and highlights conserved functions. (A) The set of 87 consistently detected genes identifiable in human and mouse macrophages at the mRNA and protein levels form 6 functionally and expression-related networks (numbered 1-6) according to the Ingenuity Knowledge Base. Expression ranking is pseudocolored in red; regulators are shown in turquoise. BP indicates biologic process; CC, cellular component; and CP, canonical pathway. Many of the genes are immune response-related, such as CD36, S100A10, S100A11, LGALS1, and LGALS3. The lysosomal cathepsins and cystatins, LAMP1, HEXA, and other catabolic enzymes are also included in this category. Furthermore, the categories oxidative phosphorylation (connected to energy pathways) and xenobiotic metabolism are overrepresented. These genes form part of the NRF2 gene targets important for redox balance. Further overrepresented categories include glucocorticoid signaling, phagocytosis, and EIF pathways; all pathways are listed in supplemental Table 1. (B) The consistent macrophage signature as a whole can be used to distinguish macrophages from other cell types. Overlap of the 500 most highly expressed genes in unrelated human GM-CSF macrophage samples (hMΦ), mouse macrophage samples (mMΦ), and even rat and chicken macrophage samples (rMΦ and chMΦ) shows a clear overrepresentation of the signature. In contrast, the consistent signature is scarcely represented when overlaid with the 500 most highly expressed genes in human, CD4 and CD8 T cells (hCD4⁺ and hCD8⁺), B cells (hB), or NK cells (hNK).