Preprint
WNK1 enforces macrophage lineage fidelity
bioRxiv : the preprint server for biology
04/28/2023
DOI: 10.1101/2023.04.26.538482
PMCID: PMC10299535
PMID: 37383948
Abstract
The appropriate development of macrophages, the body's professional phagocyte, is essential for organismal development, especially in mammals. This dependence is exemplified by the observation that loss-of-function mutations in colony stimulating factor 1 receptor (CSF1R) results in multiple tissue abnormalities owing to an absence of macrophages. Despite this importance, little is known about the molecular and cell biological regulation of macrophage development. Here, we report the surprising finding that the chloride-sensing kinase With-no-lysine 1 (WNK1) is required for development of tissue-resident macrophages (TRMs). Myeloid-specific deletion of Wnk1 resulted in a dramatic loss of TRMs, disrupted organ development, systemic neutrophilia, and mortality between 3 and 4 weeks of age. Strikingly, we found that myeloid progenitors or precursors lacking WNK1 not only failed to differentiate into macrophages, but instead differentiated into neutrophils. Mechanistically, the cognate CSF1R cytokine macrophage-colony stimulating factor (M-CSF) stimulates macropinocytosis by both mouse and human myeloid progenitors and precursor cells. Macropinocytosis, in turn, induces chloride flux and WNK1 phosphorylation. Importantly, blocking macropinocytosis, perturbing chloride flux during macropinocytosis, and inhibiting WNK1 chloride-sensing activity each skewed myeloid progenitor differentiation from macrophages into neutrophils. Thus, we have elucidated a role for WNK1 during macropinocytosis and discovered a novel function of macropinocytosis in myeloid progenitors and precursor cells to ensure macrophage lineage fidelity. HighlightsMyeloid-specific WNK1 loss causes failed macrophage development and premature deathM-CSF-stimulated myeloid progenitors and precursors become neutrophils instead of macrophagesM-CSF induces macropinocytosis by myeloid progenitors, which depends on WNK1Macropinocytosis enforces macrophage lineage commitment.
Details
- Title: Subtitle
- WNK1 enforces macrophage lineage fidelity
- Creators
- Alissa J Trzeciak - Memorial Sloan Kettering Cancer CenterWaleska Saitz Rojas - Memorial Sloan Kettering Cancer CenterZong-Lin Liu - Memorial Sloan Kettering Cancer CenterAdam S Krebs - Cornell UniversityZhaoquan Wang - Cornell UniversityPedro H V Saavedra - Memorial Sloan Kettering Cancer CenterIsabella C Miranda - Weill Cornell MedicineAllie Lipshutz - Memorial Sloan Kettering Cancer CenterJian Xie - University of IowaChou-Long Huang - University of IowaMichael Overholtzer - Kettering UniversityMichael S Glickman - Cornell UniversityChristopher N Parkhurst - Weill Cornell MedicineThomas Vierbuchen - Kettering UniversityChristopher D Lucas - Centre for Inflammation ResearchJustin S A Perry - Cornell University
- Resource Type
- Preprint
- Publication Details
- bioRxiv : the preprint server for biology
- DOI
- 10.1101/2023.04.26.538482
- PMID
- 37383948
- PMCID
- PMC10299535
- Language
- English
- Date posted
- 04/28/2023
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984438859002771
Metrics
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