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

Alissa J. Trzeciak (), Zong-Lin Liu, Mohamed Gatie, Adam S. Krebs, Waleska Saitz Rojas, Anya J. O’Neal, Ann K. Baako, Zhaoquan Wang, Justin Nelson, Isabella C. Miranda, Jazib Uddin, Allie Lipshutz, Jian Xie, Chou-Long Huang, Pedro H. V. Saavedra, Anna-Katerina Hadjantonakis, Michael Overholtzer, Michael S. Glickman, Arohan R. Subramanya, Thomas Vierbuchen, Jon Iker Etchegaray, Christopher D. Lucas, Christopher N. Parkhurst and Justin S. A. Perry ()
Additional contact information
Alissa J. Trzeciak: Memorial Sloan Kettering Cancer Center
Zong-Lin Liu: Memorial Sloan Kettering Cancer Center
Mohamed Gatie: Sloan Kettering Institute for Cancer Research
Adam S. Krebs: Memorial Sloan Kettering Cancer Center
Waleska Saitz Rojas: Memorial Sloan Kettering Cancer Center
Anya J. O’Neal: Memorial Sloan Kettering Cancer Center
Ann K. Baako: Sloan Kettering Institute for Cancer Research
Zhaoquan Wang: Memorial Sloan Kettering Cancer Center
Justin Nelson: Memorial Sloan Kettering Cancer Center
Isabella C. Miranda: Weill Cornell Medicine
Jazib Uddin: Weill Cornell Medicine
Allie Lipshutz: Memorial Sloan Kettering Cancer Center
Jian Xie: University of Iowa
Chou-Long Huang: University of Iowa
Pedro H. V. Saavedra: Northeastern University
Anna-Katerina Hadjantonakis: Memorial Sloan Kettering Cancer Center
Michael Overholtzer: Memorial Sloan Kettering Cancer Center
Michael S. Glickman: Memorial Sloan Kettering Cancer Center
Arohan R. Subramanya: University of Pittsburgh School of Medicine
Thomas Vierbuchen: Memorial Sloan Kettering Cancer Center
Jon Iker Etchegaray: Oklahoma Medical Research Foundation
Christopher D. Lucas: Queen’s Medical Research Institute
Christopher N. Parkhurst: Weill Cornell Medicine
Justin S. A. Perry: Memorial Sloan Kettering Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59901-0

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