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; Justin S A Perry

doi:10.1038/s41467-025-59901-0

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.16(1), 4945

05/28/2025

DOI: 10.1038/s41467-025-59901-0

PMCID: PMC12120055

PMID: 40436823

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https://doi.org/10.1038/s41467-025-59901-0View

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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.

Animals

Cell Differentiation - drug effects

Cell Lineage

Humans

Interferon Regulatory Factors - genetics

Interferon Regulatory Factors - metabolism

Macrophage Colony-Stimulating Factor - metabolism

Macrophage Colony-Stimulating Factor - pharmacology

Macrophages - cytology

Macrophages - drug effects

Macrophages - metabolism

Mice

Mice, Inbred C57BL

Mice, Knockout

Myeloid Progenitor Cells - cytology

Myeloid Progenitor Cells - metabolism

Neutrophils - cytology

Neutrophils - metabolism

Pinocytosis - drug effects

WNK Lysine-Deficient Protein Kinase 1 - genetics

WNK Lysine-Deficient Protein Kinase 1 - metabolism

Details

Title: Subtitle: WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity
Creators: Alissa J Trzeciak - Memorial Sloan Kettering Cancer Center
Zong-Lin Liu - Memorial Sloan Kettering Cancer Center
Mohamed Gatie - Kettering University
Adam S Krebs - Cornell University
Waleska Saitz Rojas - Memorial Sloan Kettering Cancer Center
Anya J O'Neal - Memorial Sloan Kettering Cancer Center
Ann K Baako - Kettering University
Zhaoquan Wang - Cornell University
Justin Nelson - Memorial Sloan Kettering Cancer Center
Isabella C Miranda - Weill Cornell Medicine
Jazib Uddin - Cornell University
Allie Lipshutz - Memorial Sloan Kettering Cancer Center
Jian Xie - University of Iowa
Chou-Long Huang - Department of Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Pedro H V Saavedra - Northeastern University
Anna-Katerina Hadjantonakis - Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
Michael Overholtzer - Kettering University
Michael S Glickman - Cornell University
Arohan R Subramanya - University of Pittsburgh
Thomas Vierbuchen - Kettering University
Jon Iker Etchegaray - Oklahoma Medical Research Foundation
Christopher D Lucas - Centre for Inflammation Research
Christopher N Parkhurst - Weill Cornell Medicine
Justin S A Perry - Cornell University
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 4945
DOI: 10.1038/s41467-025-59901-0
PMID: 40436823
PMCID: PMC12120055
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: NATURE PORTFOLIO; BERLIN
Grant note: 1K99HL171844 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) 5R00CA237728 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) U54DK137329 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) 5K08MH130773 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) DK111542 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK098145 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) MR/W019264/1 / RCUK | Medical Research Council (MRC) Research Scholars Award / Pew Charitable Trusts 5T32CA009149 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) MR/X019314/1 / RCUK | Medical Research Council (MRC)
Language: English
Date published: 05/28/2025
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984824175202771

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