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 - Funding Information:
This work was supported by the National Institute of Allergy and Infectious Disease (NIAID) (AI113118 and AI132653) (B.T.E.) and a Burroughs Wellcome Fund Career Award for Medical Scientists (B.T.E.). N.N.J. was supported by grant 5T32AI007163 from the NIAID. C.-C.L. was supported by the McDonnell International Scholars Academy at Washington University. S.C.-C.H. was supported by the Case Comprehensive Cancer Center American Cancer Society IRG Award (IRG−16–186–21). M.E.C. was supported by the National Science Foundation Graduate Research Fellowship program (DGE-1745038). Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. We thank E. Lantelme, A. Cullen and D. Brinja for help with fluorescence-activated cell sorting. We thank W. Beatty and L. Mwaghore for electron microscopy. We thank S. Van Dyken and C. Farnsworth for critical reading of the manuscript. We thank the members of the G. Randolph laboratory for helpful discussions about this project. We thank J. Bando, M. Robinette and T. Ai for help with flow cytometry of the gut.
Funding Information:
Mice. C57BL/6 (Taconic), B6.SJL (CD45.1, Taconic or Jackson), Il10–/– (B6.129P2-Il10tm1Cgn/J, Jackson) and LysM-Cre (B6N.129P2(B6)-Lyz2tm1(cre)Ifo/J, Jackson) mice were obtained from the vendors listed. Bhlhe40–/– (ten generations backcrossed to the C57BL/6 background)31,51, Bhlhe40GFP+(ten generations backcrossed to the C57BL/6 background)21 and Bhlhe40fl/fl (ref. 33) mice have been previously reported. The Bhlhe40GFP+ mouse strain, originally defined as STOCK Tg(Bhlhe40-EGFP)PX84Gsat/Mmucd, identification number 034730-UCD, was obtained from the Mutant Mouse Regional Resource Center (MMRRC), a National Center for Research Resources (NCRR)-NIH funded strain repository, and was donated to the MMRRC by the National Institute of Neurological Disorders and Stroke (NINDS)-funded GENSAT BAC transgenic project (The GENSAT Project, NINDS Contract N01NS02331 to the Rockefeller University). All mice were maintained in our specific pathogen-free animal facility. Sex-matched littermates were used for experiments whenever possible, although in some cases mice from multiple litters were used in a single experiment. All animal experiments were approved by the Animal Studies Committee of Washington University in St. Louis.
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 -