TY - JOUR
T1 - Bhlhe40 mediates tissue-specific control of macrophage proliferation in homeostasis and type 2 immunity
AU - Jarjour, Nicholas N.
AU - Schwarzkopf, Elizabeth A.
AU - Bradstreet, Tara R.
AU - Shchukina, Irina
AU - Lin, Chih Chung
AU - Huang, Stanley Ching Cheng
AU - Lai, Chin Wen
AU - Cook, Melissa E.
AU - Taneja, Reshma
AU - Stappenbeck, Thaddeus S.
AU - Randolph, Gwendalyn J.
AU - Artyomov, Maxim N.
AU - Urban, Joseph F.
AU - Edelson, Brian T.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065302395&partnerID=8YFLogxK
U2 - 10.1038/s41590-019-0382-5
DO - 10.1038/s41590-019-0382-5
M3 - Article
C2 - 31061528
AN - SCOPUS:85065302395
SN - 1529-2908
VL - 20
SP - 687
EP - 700
JO - Nature immunology
JF - Nature immunology
IS - 6
ER -