iRhom2 regulates CSF1R cell surface expression and non-steady state myelopoiesis in mice.
CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells. In iRhom2-/- mice, we found constitutive accumulation of membrane-bound CSF1R on myeloid cells at steady state, although cell numbers of these populations were not altered. However, in the context of mixed bone marrow (BM) chimera, under competitive pressure, iRhom2-/- BM progenitor-derived monocytes, tissue macrophages and lung DCs showed a repopulation advantage over those derived from wild-type (WT) BM progenitors, suggesting enhanced CSF1R signaling in the absence of iRhom2. In vitro experiments indicate that iRhom2-/- Lin-SCA-1+c-Kit+(LSKs) cells, but not granulocyte-macrophage progenitors (GMPs), had faster growth rates than WT cells in response to CSF1. Our results shed light on an important role of iRhom2/ADAM17 pathway in regulation of CSF1R shedding and repopulation of monocytes, macrophages and DCs.
Program in Inflammation and Autoimmunity, Hospital for Special Surgery, 535 East 71 St., New York, NY 10021, USA.
Xiaoping
X
Qing
Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Lindsay
L
Rogers
Department of Oncological Sciences, Tisch Cancer Institute and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, New York 10029, USA.
Arthur
A
Mortha
Department of Oncological Sciences, Tisch Cancer Institute and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, New York 10029, USA.
Yonit
Y
Lavin
Program in Inflammation and Autoimmunity, Hospital for Special Surgery, 535 East 71 St., New York, NY 10021, USA.
Patricia
P
Redecha
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Priya D
PD
Issuree
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Thorsten
T
Maretzky
Department of Oncological Sciences, Tisch Cancer Institute and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, New York 10029, USA.
Miriam
M
Merad
Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305.
David
D
McIlwain
Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9, Canada.
Tak W
TW
Mak
Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Christopher M
CM
Overall
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.|Department of Physiology, Systems Biology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA.
Carl P
CP
Blobel
Program in Inflammation and Autoimmunity, Hospital for Special Surgery, 535 East 71 St., New York, NY 10021, USA.|Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Jane E
JE
Salmon
D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D008168:Lung / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000502:physiology*; D038042:Myelopoiesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018183:Transplantation Chimera
D002352:Carrier Proteins; C000604004:Csf1r protein, mouse; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C569468:iRhom2 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
ADAM17; CSF1R; iRhom2; metalloprotease; myelopoiesis