التفاصيل البيبلوغرافية
| العنوان: |
WNK1 enforces macrophage lineage fidelity. |
| المؤلفون: |
Trzeciak AJ, Rojas WS, Liu ZL, Krebs AS, Wang Z, Saavedra PHV, Miranda IC, Lipshutz A, Xie J, Huang CL, Overholtzer M, Glickman MS, Parkhurst CN, Vierbuchen T, Lucas CD, Perry JSA |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 28. Date of Electronic Publication: 2023 Apr 28. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
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.
Highlights: Myeloid-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. |
| معلومات مُعتمدة: |
K08 MH130773 United States MH NIMH NIH HHS; T32 CA009149 United States CA NCI NIH HHS |
| تواريخ الأحداث: |
Date Created: 20230629 Latest Revision: 20240607 |
| رمز التحديث: |
20240607 |
| مُعرف محوري في PubMed: |
PMC10299535 |
| DOI: |
10.1101/2023.04.26.538482 |
| PMID: |
37383948 |
| قاعدة البيانات: |
MEDLINE |
