The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation.
Microarray--assisted gene--expression screens of human macrophages revealed WNT5A, a homolog of Wingless, a key regulator of Drosophila melanogaster embryonic segmentation and patterning, to be consistently up-regulated following stimulation with different mycobacterial species and conserved bacterial structures. The expression of WNT5A required Toll-like receptor signaling and NF-kappaB activation, which identifies a novel induction pathway for a Wingless homolog. We show that human peripheral-blood mononuclear cells express the WNT5A receptor Frizzled-5 (FZD5). Both WNT5A and FZD5 also were detected in granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected patients. Functional studies showed that WNT5A and FZD5 regulate the microbially induced interleukin-12 response of antigen-presenting cells and interferon-gamma production by mycobacterial antigen-stimulated T cells. Our findings implicate the evolutionarily conserved WNT/Frizzled signaling system in bridging innate and adaptive immunity to infections.
Blumenthal
Antje
A
Division of Molecular Infection Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23845 Borstel, Germany.
Ehlers
Stefan
S
Lauber
Jörg
J
Buer
Jan
J
Lange
Christoph
C
Goldmann
Torsten
T
Heine
Holger
H
Brandt
Ernst
E
Reiling
Norbert
N
D000938:Antigen-Presenting Cells / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D051157:Frizzled Receptors / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*; D000071818:Wnt-5a Protein
D000942:Antigens, Bacterial; C498589:FZD5 protein, human; D051157:Frizzled Receptors; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein