Abstract
CO2 is produced during aerobic respiration. Normally, levels of CO2 in the blood are tightly regulated but pCO2 can rise (hypercapnia, pCO2 > 45 mmHg) in patients with lung diseases, for example, chronic obstructive pulmonary disease (COPD). Hypercapnia is a risk factor in COPD but may be of benefit in the context of destructive inflammation. The effects of CO2 per se, on transcription, independent of pH change are poorly understood and warrant further investigation. Here we elucidate the influence of hypercapnia on monocytes and macrophages through integration of state-of-the-art RNA-sequencing, metabolic and metabolomic approaches. THP-1 monocytes and interleukin 4–polarized primary murine macrophages were exposed to 5% CO2 versus 10% CO2 for up to 24 h in pH-buffered conditions. In hypercapnia, we identified around 370 differentially expressed genes (DEGs) under basal and about 1889 DEGs under lipopolysaccharide-stimulated conditions in monocytes. Transcripts relating to both mitochondrial and nuclear-encoded gene expression were enhanced in hypercapnia in basal and lipopolysaccharide-stimulated cells. Mitochondrial DNA content was not enhanced, but acylcarnitine species and genes associated with fatty acid metabolism were increased in hypercapnia. Primary macrophages exposed to hypercapnia also increased activation of genes associated with fatty acid metabolism and reduced activation of genes associated with glycolysis. Thus, hypercapnia elicits metabolic shifts in lipid metabolism in monocytes and macrophages under pH-buffered conditions. These data indicate that CO2 is an important modulator of monocyte transcription that can influence immunometabolic signaling in immune cells in hypercapnia. These immunometabolic insights may be of benefit in the treatment of patients experiencing hypercapnia.
Original language | English (US) |
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Pages (from-to) | 556-577 |
Number of pages | 22 |
Journal | Immunology and Cell Biology |
Volume | 101 |
Issue number | 6 |
DOIs | |
State | Published - Jul 2023 |
Funding
We acknowledge the support of the Conway Institute Transcriptomics Core Facility led by Dr Catherine Moss, the Conway Institute Flow Cytometry Core Facility led by Dr Alfonso Blanco and the Conway Institute Metabolomics Core Facility led by Professor Lorraine Brennan, the University College Dublin Veterinary Sciences Centre Transcriptomics Laboratory supported by Professor Stephen Gordon and Dr John Browne. Open access funding provided by IReL. This work was supported by a Science Foundation Ireland (SFI) Career Development award to EPC (SFI 15/CDA/3490) which also supported DEP and CM. MS and JIS are supported by the NIH grant HL‐147070. JCM and LC are supported by SFI award (SFI/FRL/4863). This research was supported in part by The Comprehensive Molecular Analytical Platform (CMAP) under The SFI Research Infrastructure Programme, reference 18/RI/5702. This research was supported in part by the SFI Research Infrastructure Programme 15/RI/3215.
Keywords
- Acylcarnitine
- CO
- RNA-seq
- carbon dioxide
- gene expression
- hypercapnia
- mitochondria
- monocyte
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Cell Biology