iRhom2 regulates CSF1R cell surface expression and non‐steady state myelopoiesis in mice |
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| Authors: | Xiaoping Qing Lindsay D. Rogers Arthur Mortha Yonit Lavin Patricia Redecha Priya D. Issuree Thorsten Maretzky Miriam Merad David R. McIlwain Tak W. Mak Christopher M. Overall Jane E. Salmon |
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| Affiliation: | 1. Program in Inflammation and Autoimmunity, Hospital for Special Surgery, New York, NY, USA;2. Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada;3. Department of Oncological Sciences, Tisch Cancer Institute and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA;4. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA;5. Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA;6. Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada;7. Department of Medicine, Weill Medical College of Cornell University, New York, NY, USAThese authors contributed equally to this work as senior co‐authors. |
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| Abstract: | 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. |
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| Keywords: | ADAM17 CSF1R iRhom2 metalloprotease myelopoiesis |
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