Transcriptomic Profiling Reveals That HMGB1 Induces Macrophage Polarization Different from Classical M1

Biomolecules. 2022 Jun 2;12(6):779. doi: 10.3390/biom12060779.

Abstract

Macrophages are key inflammatory immune cells that display dynamic phenotypes and functions in response to their local microenvironment. In different conditions, macrophage polarization can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity via the Toll-like receptor (TLR) 4, the receptor for advanced glycation end products (RAGE), and C-X-C chemokine receptor (CXCR) 4. This study investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) stimulated with different HMGB1 redox isoforms using bulk RNA sequencing (RNA-Seq). Disulfide HMGB1 (dsHMGB1)-stimulated BMDMs showed a similar but distinct transcriptomic profile to LPS/IFNγ- and LPS-stimulated BMDMs. Fully reduced HMGB1 (frHMGB1) did not induce any significant transcriptomic change. Interestingly, compared to LPS/IFNγ- and LPS-, dsHMGB1-stimulated BMDMs showed lipid metabolism and foam cell differentiation gene set enrichment, and oil red O staining revealed that both dsHMGB1 and frHMGB1 alleviated oxidized low-density lipoprotein (oxLDL)-induced foam cells formation. Overall, this work, for the first time, used transcriptomic analysis by RNA-Seq to investigate the impact of HMGB1 stimulation on BMDM polarization. Our results demonstrated that dsHMGB1 and frHMGB1 induced distinct BMDM polarization phenotypes compared to LPS/IFNγ- and LPS- induced phenotypes.

Keywords: HMGB1; RNA sequencing; foam cell formation; gene ontology; macrophage polarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HMGB1 Protein* / genetics
  • HMGB1 Protein* / metabolism
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation*
  • Macrophages / metabolism
  • Mice
  • Transcriptome*

Substances

  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Lipopolysaccharides

Grants and funding

This research received grants from The Swedish Rheumatism Association, King Gustaf V and Queen Victoria’s Foundation of Freemasons, Karolinska Institute Foundations, and the Swedish Science Council (grant no 2018-02885 to H.E.H.). H.Q. was supported by grants from the China Scholarship Council (Grant No. 201807930002).