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Novel metabolic adaptation promotes enhanced macrophage efferocytosis under a limited-oxygen environment

UID: 11209

Author(s): Wang, Ya-Ting*, Trzeciak, Alissa J.*, Rojas, Waleska Saitz*, Saavedra, Pedro*, Chen, Yan-Ting*, Chirayil, Rachel*, Iker Etchegaray, J., Lucas, Christopher D., Puleston, Daniel J., Keshari, Kayvan R.*, Perry, Justin S. A.* * MSK affiliated

Description
Summary from GEO:

"Apoptotic cell clearance (efferocytosis), a process essential for organismal homeostasis, is performed by phagocytes that inhabit a wide range of environments, including physiologic hypoxia. Here, we find macrophages, the predominant tissue-resident phagocyte, display enhanced efferocytosis under chronic hypoxia, characterized by increased internalization and accelerated degradation of apoptotic cells. Analysis of mRNA and protein programs revealed that chronic hypoxia induces two distinct but complimentary states in macrophages. The first, ‘primed’ state consists of concomitant induction of transcriptional and translational programs broadly associated with metabolism in apoptotic cell-naïve macrophages that persist during efferocytosis. The second, ‘poised’ state consists of transcription, but not translation, of phagocyte function programs in apoptotic cell-naïve macrophages that are subsequently translated during efferocytosis. We discovered that one such primed state consists of the efficient flux of glucose into a noncanonical pentose phosphate pathway (PPP) loop, whereby PPP-derived intermediates cycle back through the PPP to enhance production of NADPH. Mechanistically, we found that PPP-derived NADPH directly supports enhanced efferocytosis under chronic hypoxia via its role in phagolysosomal maturation, while simultaneously maintaining cellular redox homeostasis. Thus, macrophages adapt to chronic hypoxia by adopting states that both support cell fitness and ensure ability to rapidly and safely perform essential homeostatic functions."

Overall design from GEO:

"The experiment consists of three conditions: Phagocytes (primary macrophages) condition in standard oxygen, acute hypoxia, or chronic hypoxia. All conditions consisted of three biological replicates."
Subject of Study
Mus musculus
Subject(s)
Efferocytosis
Hypoxia
Macrophages
MicroRNAs
Pentose Phosphate Pathway
Access via GEO


Accession #: GSE192969

Access via BioProject


Accession #: PRJNA793903

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications
Wang Y, Trzeciak A, Rojas W, Saavedra P, Chen Y, Chirayil R, Etchegaray J, Lucas C, Puleston D, Keshari K, Perry J. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments. Cell Metabolism. 2023; 35(2):316-331.e6.
Equipment Used
Illumina NovaSeq 6000
Dataset Format(s)
TXT
Dataset Size
1.6 MB
Data Catalog Record Updated
2024-03-27