Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages.
At the earliest stage of activation, human polymorphonuclear neutrophils release vesicles derived directly from the cell surface. These vesicles, called ectosomes (PMN-Ect), expose phosphatidylserine in the outer membrane leaflet. They inhibit the inflammatory response of human monocyte-derived macrophages and dendritic cells to zymosan A (ZymA) and LPS and induce TGF-β1 release, suggesting a reprogramming toward a tolerogenic phenotype. The receptors and signaling pathways involved have not yet been defined. Here, we demonstrate that PMN-Ect interfered with ZymA activation of macrophages via inhibition of NFκB p65 phosphorylation and NFκB translocation. The MerTK (Mer receptor tyrosine kinase) and PI3K/Akt pathways played a key role in this immunomodulatory effect as shown using specific MerTK-blocking antibodies and PI3K inhibitors LY294002 and wortmannin. As a result, PMN-Ect reduced the transcription of many proinflammatory genes in ZymA-activated macrophages. In sum, PMN-Ect interacted with the macrophages by activation of the MerTK pathway responsible for down-modulation of the proinflammatory signals generated by ZymA.
Eken
Ceylan
C
Basel University Hospital, 4031 Basel, Switzerland. ceylan.eken@unibas.ch
Martin
Perrine J
PJ
Sadallah
Salima
S
Treves
Susan
S
Schaller
Monica
M
Schifferli
Jürg A
JA
D000730:Androstadienes / Q000494:pharmacology; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000077191:Wortmannin; D015054:Zymosan / Q000494:pharmacology; D000076202:c-Mer Tyrosine Kinase
D000730:Androstadienes; D002867:Chromones; D008070:Lipopolysaccharides; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D015054:Zymosan; D019869:Phosphatidylinositol 3-Kinases; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin