WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity
Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1r<sup>iCre</sup>-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.
Authors
- Christopher D. Lucas (ORCID: https://orcid.org/0000-0002-7523-0295)
- Jazib Uddin (ORCID: https://orcid.org/0000-0001-5303-5213)
- Michael S. Glickman (ORCID: https://orcid.org/0000-0001-7918-5164)
- Anna‐Katerina Hadjantonakis (ORCID: https://orcid.org/0000-0002-7580-5124)
- Allie Lipshutz (ORCID: https://orcid.org/0000-0002-1786-7300)
- Zhaoquan Wang (ORCID: https://orcid.org/0000-0001-8227-0941)
- Thomas Vierbuchen (ORCID: https://orcid.org/0000-0002-5690-5680)
- Jian Xie (ORCID: https://orcid.org/0000-0001-9454-1358)
- Alissa J. Trzeciak (ORCID: https://orcid.org/0000-0002-4518-0098)
- Christopher N. Parkhurst (ORCID: https://orcid.org/0000-0003-1725-3939)
- Chou‐Long Huang (ORCID: https://orcid.org/0000-0001-9963-3040)
- Isabella C. Miranda
- Zong-Lin Liu
- Arohan R. Subramanya (ORCID: https://orcid.org/0000-0002-2609-7643)
- Michael Overholtzer (ORCID: https://orcid.org/0000-0003-3007-4986)
- Pedro Saavedra (ORCID: https://orcid.org/0000-0002-7659-4533)
- Anya J. O’Neal (ORCID: https://orcid.org/0000-0001-5188-1344)
- Mohamed I. Gatie (ORCID: https://orcid.org/0000-0001-8500-5609)
- Justin S. A. Perry (ORCID: https://orcid.org/0000-0003-4063-6524)
- Jon Iker Etchegaray (ORCID: https://orcid.org/0000-0002-5757-2734)
- Waleska Saitz Rojas
- Justin Nelson (ORCID: https://orcid.org/0000-0001-5488-5850)
- Adam Krebs
- Ann K Baako
Institutions
- University of Iowa (US)
- Northeastern University (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Pittsburgh (US)
- Cornell University (US)
- Oklahoma Medical Research Foundation (US)
- Kettering University (US)
- MRC Centre for Regenerative Medicine (GB)
- Centre for Inflammation Research (GB)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-28
- DOI
- https://doi.org/10.1038/s41467-025-59901-0
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Pew Charitable Trusts
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- Pittsburgh Center for Kidney Research, University of Pittsburgh
- Medical Research Council
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases