Monocyte to macrophage differentiation goes along with modulation of the plasmalogen pattern through transcriptional regulation

PLoS One. 2014 Apr 8;9(4):e94102. doi: 10.1371/journal.pone.0094102. eCollection 2014.

Abstract

Background: Dysregulation of monocyte-macrophage differentiation is a hallmark of vascular and metabolic diseases and associated with persistent low grade inflammation. Plasmalogens represent ether lipids that play a role in diabesity and previous data show diminished plasmalogen levels in obese subjects. We therefore analyzed transcriptomic and lipidomic changes during monocyte-macrophage differentiation in vitro using a bioinformatic approach.

Methods: Elutriated monocytes from 13 healthy donors were differentiated in vitro to macrophages using rhM-CSF under serum-free conditions. Samples were taken on days 0, 1, 4 and 5 and analyzed for their lipidomic and transcriptomic profiles.

Results: Gene expression analysis showed strong regulation of lipidome-related transcripts. Enzymes involved in fatty acid desaturation and elongation were increasingly expressed, peroxisomal and ER stress related genes were induced. Total plasmalogen levels remained unchanged, while the PE plasmalogen species pattern became more similar to circulating granulocytes, showing decreases in PUFA and increases in MUFA. A partial least squares discriminant analysis (PLS/DA) revealed that PE plasmalogens discriminate the stage of monocyte-derived macrophage differentiation. Partial correlation analysis could predict novel potential key nodes including DOCK1, PDK4, GNPTAB and FAM126A that might be involved in regulating lipid and especially plasmalogen homeostasis during differentiation. An in silico transcription analysis of lipid related regulation revealed known motifs such as PPAR-gamma and KLF4 as well as novel candidates such as NFY, RNF96 and Zinc-finger proteins.

Conclusion: Monocyte to macrophage differentiation goes along with profound changes in the lipid-related transcriptome. This leads to an induction of fatty-acid desaturation and elongation. In their PE-plasmalogen profile macrophages become more similar to granulocytes than monocytes, indicating terminal phagocytic differentiation. Therefore PE plasmalogens may represent potential biomarkers for cell activation. For the underlying transcriptional network we were able to predict a range of novel central key nodes and underlying transcription factors using a bioinformatic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / physiology*
  • Gene Expression Regulation / physiology*
  • Humans
  • Macrophages / cytology*
  • Macrophages / metabolism
  • Monocytes / cytology*
  • Monocytes / metabolism
  • Plasmalogens / metabolism*
  • Transcriptome

Substances

  • Plasmalogens

Grant support

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 202272, IP-Project LipidomicNet. The project was also supported by the Deutsche Forschungsgemeinschaft (SFB-TR 13/A3), related to “The European Lipidomics Initiative; shaping the life sciences” a specific support action subsidized by the EC 2006-2007 (proposal number 013032). The results upon which this publication is based were partly funded by the Federal Ministry of Education and Research under the Project Number FKZ01KU1216J. The responsibility for the content of this publication lies with the author. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.