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Von Hippel-Lindau Protein Is Required for Optimal Alveolar Macrophage Terminal Differentiation, Self-Renewal, and Function.

Authors
  • Izquierdo, Helena M1
  • Brandi, Paola1
  • Gómez, Manuel-José1
  • Conde-Garrosa, Ruth1
  • Priego, Elena1
  • Enamorado, Michel1
  • Martínez-Cano, Sarai1
  • Sánchez, Iria1
  • Conejero, Laura1
  • Jimenez-Carretero, Daniel1
  • Martín-Puig, Silvia1
  • Guilliams, Martin2
  • Sancho, David3
  • 1 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain. , (Spain)
  • 2 Laboratory of Myeloid Cell Ontogeny and Functional Specialisation, VIB-UGhent Centre for Inflammation Research, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium. , (Belgium)
  • 3 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain. Electronic address: [email protected] , (Spain)
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Aug 14, 2018
Volume
24
Issue
7
Pages
1738–1746
Identifiers
DOI: 10.1016/j.celrep.2018.07.034
PMID: 30110631
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11cΔVhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11cΔVhl mice do not reverse pulmonary alveolar proteinosis when transplanted into Csf2rb-/- mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their intact oxygen-sensing capacity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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