A New Immunomodulatory Role for Peroxisomes in Macrophages Activated by the TLR4 Ligand Lipopolysaccharide.
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 genePex14orMfp2markedly 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.
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.|Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
Vijith
V
Vijayan
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Tumpara
T
Srinu
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Srikanth
S
Karnati
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.|Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392 Giessen, Germany.
Vannuruswamy
V
Garikapati
Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria; and.
Monika
0000-0001-7410-736X
M
Linke
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Lilit
L
Kamalyan
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Srihari Reddy
SR
Mali
Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
Kritika
K
Sudan
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany.
Andreas
A
Kollas
Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60596 Frankfurt, Germany.
Tobias
T
Schmid
Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392 Giessen, Germany.
Sabine
S
Schulz
Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392 Giessen, Germany.
Bernhard
B
Spengler
Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria; and.
Thomas
0000-0002-4349-0797
T
Weichhart
Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
Stephan
S
Immenschuh
Institute for Anatomy and Cell Biology II, Medical Cell Biology, Justus Liebig University Giessen, 35392 Giessen, Germany; Eveline.Baumgart-Vogt@anatomie.med.uni-giessen.de.
Eveline
0000-0002-8265-3763
E
Baumgart-Vogt
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics; D020675:Peroxisomes / Q000276:immunology*; D010654:Phenylbutyrates / Q000378:metabolism*; D061251:Primary Cell Culture; D000067996:RAW 264.7 Cells; D012097:Repressor Proteins / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C499193:Pex14 protein, mouse; D010654:Phenylbutyrates; D012097:Repressor Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004281:Docosahexaenoic Acids; C491288:Hsd17b4 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D064029:Peroxisomal Multifunctional Protein-2