Identification of an atypical monocyte and committed progenitor involved in fibrosis

• Published in: Nature (London) Vol. 541; no. 7635; pp. 96 - 101
• Main Authors: Satoh, Takashi, Nakagawa, Katsuhiro, Sugihara, Fuminori, Kuwahara, Ryusuke, Ashihara, Motooki, Yamane, Fumihiro, Minowa, Yosuke, Fukushima, Kiyoharu, Ebina, Isao, Yoshioka, Yoshichika, Kumanogoh, Atsushi, Akira, Shizuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-01-2017; Nature Publishing Group
• Subjects: 631/250/2504/342; 631/250/262; Adoptive Transfer; Animals; Antigens, CD - metabolism; Antigens, Ly - metabolism; Biomarkers - metabolism; Bleomycin - toxicity; Bone marrow; CCAAT-Enhancer-Binding Protein-beta - deficiency; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Adhesion Molecules - metabolism; Cell Differentiation; Dendritic Cells - cytology; Disease; Disease Models, Animal; Fibroblasts; Fibrosis; Gene expression; Granulocyte-Macrophage Progenitor Cells - cytology; Granulocyte-Macrophage Progenitor Cells - metabolism; Granulocytes; Granulocytes - cytology; Granulocytes - metabolism; Health aspects; Humanities and Social Sciences; Inflammation; letter; Leukocytes; Macrophages; Male; Mice; Molecular Targeted Therapy - trends; Monocytes; Monocytes - classification; Monocytes - metabolism; Monocytes - pathology; Monocytes - transplantation; multidisciplinary; Pathogenesis; Physiological aspects; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Receptors, IgE - metabolism; Scavenger Receptors, Class A - metabolism; Science
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20611

An atypical monocyte with partial granulocyte characteristics is identified and shown to be critical for the development of fibrosis.
An immunological cell type inducing liver fibrosis
In this study, Shizuo Akira and colleagues identify a previously unknown monocyte–granulocyte hybrid cell type as being critical to the development of bleomycin-induced pulmonary fibrosis in mice, the most commonly used experimental study model of human lung fibrosis. The cells, termed segregated-nucleus-containing atypical monocytes (SatMs), are differentiated from committed progenitor cells under the control of the transcription factor C/EBPβ. The authors speculate that SatMs, and other reported 'disorder-specific monocyte/macrophage subtypes' corresponding to certain diseases, might be investigated as highly specific therapeutic targets.
Monocytes and macrophages comprise a variety of subsets with diverse functions
1
,
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 macrophages
6
,
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.