2. Academic Validation
  3. Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry

Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry

  • Cell Rep. 2024 Jul 23;43(7):114471. doi: 10.1016/j.celrep.2024.114471.
Bo Meng 1,  Na Zhao 2,  Petra Mlcochova 3,  Isabella A T M Ferreira 3,  Brian M Ortmann 3,  Tanja Davis 2,  Niek Wit 3,  Jan Rehwinkel 2,  Simon Cook 4,  Patrick H Maxwell 5,  James A Nathan 3,  Ravindra K Gupta 6
Affiliations

Affiliations

  • 1 Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: bm432@cam.ac.uk.
  • 2 University of Oxford, Oxford, UK.
  • 3 Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK.
  • 4 Babraham Institute, Cambridge, UK.
  • 5 School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • 6 Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK; Africa Health Research Institute, Durban, KwaZulu Natal, South Africa. Electronic address: rkg20@cam.ac.uk.
PMID: 38996069 DOI: 10.1016/j.celrep.2024.114471
Abstract

Low-oxygen conditions (hypoxia) have been associated primarily with cell-cycle arrest in dividing cells. Macrophages are typically quiescent in G0 but can proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in macrophages. Cell cycle progression is largely limited to G0-G1/S phase transition with little progression to G2/M. This cell cycle transitioning is triggered by an HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell-cycle-associated proteins, including CDK1, which is known to phosphorylate SAMHD1 at T592 and thereby regulate Antiviral activity. Prolyl hydroxylase (PHD) inhibitors are able to recapitulate HIF2α-dependent cell cycle entry in macrophages. Finally, tumor-associated macrophages (TAMs) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at the single-cell level. These findings have implications for inflammation and tumor progression/metastasis where low-oxygen environments are common.

Keywords

CDK1; CP: Immunology; SAMHD1; TAM; cell cycle; hypoxia; lentivurus; low oxygen; macrophage; tumor.

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