Monocytes and macrophages comprise a variety of subsets with diverse functions1,2,3,4,5. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages6,7,8. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1+Msr1+Ly6C−F4/80−Mac1+ monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein β (C/EBPβ), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb−/− haematopoietic cells. Adoptive transfer of SatM into Cebpb−/− mice resulted in fibrosis. Notably, SatM are derived from Ly6C−FcεRI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C−FcεRI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPβ licenses differentiation of SatM from their committed progenitor.
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We thank S. Saeki, S. Watanabe, R. Takenaka and M. Miyamoto for assistance with experiments, and T. Matsuki, T. Kawasaki, H. Kanemaru, H. Tanaka and K. Kuniyoshi for helpful discussions. We thank T. Kitamura for providing PlatE cells. We also thank E. Kamada for secretarial assistance, and C. Funamoto, N. Kitagaki, A. Wataki, K. Yokoyama and R. Kawaguchi for technical assistance. This work was supported by the Government of Japan and the Japan Society for the Promotion of Science (JSPS) through the funding program for World-Leading Innovative R&D on Science and Technology (FIRST Program), by Japan Science and Technology Agency (JST) thorough funding for a Grant-in-Aid for Young Scientists (A)(16H06234), Specially Promoted Research (15H05704) and the US National Institutes of Health (P01-AI070167) and ‘Visionary Research Fund’ from Takeda Science Foundation. A part of this work was supported by the Nanotechnology Platform (project number 12024046) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
Extended data figures
The animation shows lung of WT chimeric in normal condition.The images were taken by MRI at day 0.
The animation shows inflamed area (red) in lung of WT chimeric. The images were taken by MRI after 4 days BLM administration.
The animation shows inflamed area (red) in lung of C/ebpb–/– chimeric mice. The images were taken by MRI after 4 days BLM administration.
The animation shows fibrotic area (blue) in lung of WT chimeric mice. The images were taken by MRI after 14 days BLM administration.
The animation shows fibrotic area (blue) in lung of C/ebpb–/– chimeric mice. The images were taken by MRI after 14 days BLM administration.
SatM was sorted from BM, and the Image was taken by STEM.
SMP was sorted from BM, and the Image was taken by STEM.