A New Immunomodulatory Role for Peroxisomes in Macrophages Activated by the TLR4 Ligand Lipopolysaccharide

J Immunol. 2017 Mar 15;198(6):2414-2425. doi: 10.4049/jimmunol.1601596. Epub 2017 Feb 8.


Peroxisomes are proposed to play an important role in the regulation of systemic inflammation; however, the functional role of these organelles in inflammatory responses of myeloid immune cells is largely unknown. In this article, we demonstrate that the nonclassical peroxisome proliferator 4-phenyl butyric acid is an efficient inducer of peroxisomes in various models of murine macrophages, such as primary alveolar and peritoneal macrophages and the macrophage cell line RAW264.7, but not in primary bone marrow-derived macrophages. Further, proliferation of peroxisomes blocked the TLR4 ligand LPS-induced proinflammatory response, as detected by the reduced induction of the proinflammatory protein cyclooxygenase (COX)-2 and the proinflammatory cytokines TNF-α, IL-6, and IL-12. In contrast, disturbing peroxisome function by knockdown of peroxisomal gene Pex14 or Mfp2 markedly increased the LPS-dependent upregulation of the proinflammatory proteins COX-2 and TNF-α. Specifically, induction of peroxisomes did not affect the upregulation of COX-2 at the mRNA level, but it reduced the half-life of COX-2 protein, which was restored by COX-2 enzyme inhibitors but not by proteasomal and lysosomal inhibitors. Liquid chromatography-tandem mass spectrometry analysis revealed that various anti-inflammatory lipid mediators (e.g., docosahexaenoic acid) were increased in the conditioned medium from peroxisome-induced macrophages, which blocked LPS-induced COX-2 upregulation in naive RAW264.7 cells and human primary peripheral blood-derived macrophages. Importantly, LPS itself induced peroxisomes that correlated with the regulation of COX-2 during the late phase of LPS activation in macrophages. In conclusion, our findings identify a previously unidentified role for peroxisomes in macrophage inflammatory responses and suggest that peroxisomes are involved in the physiological cessation of macrophage activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Docosahexaenoic Acids / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / immunology
  • Macrophage Activation*
  • Macrophages / immunology*
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Peroxisomal Multifunctional Protein-2 / genetics
  • Peroxisomes / immunology*
  • Phenylbutyrates / metabolism*
  • Primary Cell Culture
  • RAW 264.7 Cells
  • Repressor Proteins / genetics
  • Toll-Like Receptor 4 / metabolism*


  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • Membrane Proteins
  • Pex14 protein, mouse
  • Phenylbutyrates
  • Repressor Proteins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Docosahexaenoic Acids
  • Hsd17b4 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Peroxisomal Multifunctional Protein-2