Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10.
OBJECTIVE
Sepsis is a major cause of death for intensive care patients. High concentrations of inflammatory cytokines are characteristic of severe systemic inflammation and activated monocytes are their predominant cellular source. To identify targets for antiinflammatory intervention, we investigated the response of human macrophages to inflammatory and antiinflammatory mediators.


RESULTS
We profiled gene expression in human macrophages exposed to lipopolysaccharide (LPS) and interferon (IFN)-gamma in the presence or absence of recombinant activated protein C (APC) or IL-10 and identified Wnt5A as one of the transcripts most highly induced by LPS/IFN-gamma and suppressed by APC and IL-10. We confirmed regulation of Wnt5A protein in macrophages and detected it in sera and bone marrow macrophages of patients with severe sepsis. We established that a functional Wnt5A/frizzled-5/CaMKII signaling pathway was essential for macrophage inflammatory activation. To prove the essential contribution of Wnt5A we measured inflammatory cytokines after stimulation with Wnt5A, silenced Wnt5A by siRNA, and blocked receptor binding with soluble Frizzled-related peptide-1 (sFRP1).


CONCLUSIONS
Wnt5A is critically involved in inflammatory macrophage signaling in sepsis and is a target for antiinflammatory mediators like APC or antagonists like sFRP1.
Pereira
Claudia
C
Molecular and Clinical Inflammation Research Unit, Medical Clinic, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland.
Schaer
Dominik J
DJ
Bachli
Esther B
EB
Kurrer
Michael O
MO
Schoedon
Gabriele
G
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D018836:Inflammation Mediators / Q000032:analysis; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D011486:Protein C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011486:Protein C; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D016753:Interleukin-10; D007371:Interferon-gamma; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2