2. Academic Validation
  3. WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity

WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity

  • Nat Commun. 2025 May 28;16(1):4945. doi: 10.1038/s41467-025-59901-0.
Alissa J Trzeciak 1,  Zong-Lin Liu 2 3,  Mohamed Gatie 4,  Adam S Krebs 2 5,  Waleska Saitz Rojas 2,  Anya J O'Neal 2,  Ann K Baako 4 5,  Zhaoquan Wang 2 5,  Justin Nelson 3,  Isabella C Miranda 6,  Jazib Uddin 7,  Allie Lipshutz 2,  Jian Xie 8,  Chou-Long Huang 8,  Pedro H V Saavedra 9,  Anna-Katerina Hadjantonakis 3 4,  Michael Overholtzer 3 10,  Michael S Glickman 2 3 5 11,  Arohan R Subramanya 12,  Thomas Vierbuchen 3 4,  Jon Iker Etchegaray # 13,  Christopher D Lucas # 14 15,  Christopher N Parkhurst # 6,  Justin S A Perry 16 17 18
Affiliations

Affiliations

  • 1 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. trzeciaa@mskcc.org.
  • 2 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.
  • 5 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA.
  • 6 Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 7 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA.
  • 8 Department of Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 9 Department of Biology, Northeastern University, Boston, MA, USA.
  • 10 Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.
  • 11 Division of Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 12 Dept of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 13 Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
  • 14 University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, BioQuarter, UK.
  • 15 Institute for Regeneration and Repair, Edinburgh, BioQuarter, UK.
  • 16 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. perryj@mskcc.org.
  • 17 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. perryj@mskcc.org.
  • 18 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA. perryj@mskcc.org.
  • # Contributed equally.
PMID: 40436823 DOI: 10.1038/s41467-025-59901-0
Abstract

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 Csf1riCre-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.

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