Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentiviral transduction
Abstract Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2α-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2α driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 20. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Bo [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.12.15.571908 |
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| PPN (Katalog-ID): |
XBI041889320 |
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| 520 | |a Abstract Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2α-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2α driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence. | ||
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| 700 | 1 | |a Zhao, Na |4 aut | |
| 700 | 1 | |a Mlcochova, Petra |4 aut | |
| 700 | 1 | |a Ferreira, Isabella A.T.M |4 aut | |
| 700 | 1 | |a Ortmann, Brian M. |4 aut | |
| 700 | 1 | |a Davis, Tanja |4 aut | |
| 700 | 1 | |a Wit, Niek |4 aut | |
| 700 | 1 | |a Rehwinkel, Jan |4 aut | |
| 700 | 1 | |a Cook, Simon |4 aut | |
| 700 | 1 | |a Maxwell, Patrick H. |4 aut | |
| 700 | 1 | |a Nathan, James A. |4 aut | |
| 700 | 1 | |a Gupta, Ravindra K. |0 (orcid)0000-0001-9751-1808 |4 aut | |
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