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

Abstract

SummaryThe 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.

The E3 ligase VHL controls alveolar macrophage function via metabolic–epigenetic regulation

“…We have shown that absence of VHL caused glycolytic upshift, impaired mitochondrial respiration capacity, and altered signature gene expression of AMs in a HIF1α-dependent manner. Interestingly, one recent study has shown that VHL plays a critical role in AM terminal differentiation, self-renews, and functions at steady state by using the Vhl fl/fl CD11c -Cre mice (Izquierdo et al, 2018). Consistently, we detected foamy AM morphology, abnormal terminal differentiation markers, and impaired proliferation during inflammation upon loss of VHL.…”

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

“…A recent study has revealed an indispensable role of von Hippel-Lindau protein (VHL), a negative regulator of hypoxia-inducible factors (HIFs), in the terminal differentiation of AMs [34]. Self-renewal capacity was severely impaired in AMs that were selectively depleted of Vhl gene.…”

Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine-tuning of GM-CSF receptor signaling

“…In contrast to Ssu72-deficient AMs, Ssu72-deficient IMs showed no defects in the cell cycle or cyclin expression ( Fig 3, D and E). Results from the in vivo BrdU incorporation assay 19 in LysM-CreSsu72 fl/fl mice showed that the rate of BrdU uptake in mature AMs at day 1 versus at day 7 after BrdU injection was lower than in LysM-Cre mice. This indicated that turnover of mature Ssu72-deficient AMs is lower than that of mature WT AMs (Fig 3, F).…”