Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity

Nicholas N. Jarjour, Elizabeth A. Schwarzkopf, Tara R. Bradstreet, Irina Shchukina, Chih Chung Lin, Stanley Ching Cheng Huang, Chin Wen Lai, Melissa E. Cook, Reshma Taneja, Thaddeus S. Stappenbeck, Gwendalyn J. Randolph, Maxim N. Artyomov, Joseph F. Urban, Brian T. Edelson

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)687-700
Number of pages14
JournalNature immunology
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2019

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