301. Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity.
- Author
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Jarjour NN, Schwarzkopf EA, Bradstreet TR, Shchukina I, Lin CC, Huang SC, Lai CW, Cook ME, Taneja R, Stappenbeck TS, Randolph GJ, Artyomov MN, Urban JF Jr, and Edelson BT
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Biomarkers, Cell Cycle genetics, Cell Cycle immunology, Cell Proliferation, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Helicobacter Infections genetics, Helicobacter Infections immunology, Helicobacter pylori immunology, Homeodomain Proteins metabolism, Immunophenotyping, Macrophages, Peritoneal immunology, Macrophages, Peritoneal metabolism, Mice, Mice, Transgenic, Monocytes immunology, Monocytes metabolism, Organ Specificity genetics, Organ Specificity immunology, Transcriptome, Basic Helix-Loop-Helix Transcription Factors genetics, Homeodomain Proteins genetics, Homeostasis genetics, Homeostasis immunology, Immunity genetics, Macrophages immunology, Macrophages metabolism
- Abstract
Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.
- Published
- 2019
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