Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression

Tissue-resident macrophages are derived from different precursor cells and display different phenotypes. Reconstitution of the tissue-resident macrophages of inflamed or damaged tissues in adults can be achieved by bone marrow-derived monocytes/macrophages. Using lysozyme (Lysm)-GFP-reporter mice, we found that alveolar macrophages (AMs), Kupffer cells, red pulp macrophages (RpMacs), and kidney-resident macrophages were Lysm-GFP^-, whereas all monocytes in the fetal liver, adult bone marrow, and blood were Lysm-GFP⁺. Donor-derived Lysm-GFP⁺ resident macrophages gradually became Lysm-GFP^- in recipients and developed gene expression profiles characteristic of tissue-resident macrophages. Thus, Lysm may be used to distinguish newly formed and long-term surviving tissue-resident macrophages that were derived from bone marrow precursor cells in adult mice under pathological conditions. Furthermore, we found that Irf4 might be essential for resident macrophage differentiation in all tissues, while cytokine and receptor pathways, mTOR signaling pathways, and fatty acid metabolic processes predominantly regulated the differentiation of RpMacs, Kupffer cells, and kidney macrophages, respectively. Deficiencies in ST2, mechanistic target of rapamycin (mTOR) and fatty acid-binding protein 5 (FABP5) differentially impaired the differentiation of tissue-resident macrophages from bone marrow-derived monocytes/macrophages in the lungs, liver, and kidneys. These results indicate that a combination of shared and unique signaling pathways coordinately shape tissue-resident macrophage differentiation in various tissues.