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Blood, 1 August 2006, Vol. 108, No. 3, pp. 784.
Macrophage activation:'tis the way the WNT blowsUNIVERSITY OF NOTRE DAME
Wnt5a and its receptor Frizzled-5 are up-regulated in human macrophages upon Mycobacterium tuberculosis infection, and their expression promotes IL-12 production and T-cell activation, demonstrating a previously undescribed link between Wnt signaling and innate and acquired immune responses.
The studies stemmed from a microarray-based gene expression screen that revealed that Wnt5a mRNA expression was up-regulated 3- to 5-fold in human macrophages infected with M tuberculosis, or treated with LPS or Pam3CSK2. Of interest, the induction of Wnt5a by M tuberculosis and LPS was dependent on TLR2 and TLR4, respectively, and both stimuli required NF-  B activation. This is a previously undescribed pathway for inducing Wnt expression. The authors also established that the Wnt5a receptor Frizzled-5 was up-regulated in macrophages infected with M tuberculosis, although to a lesser extent relative to treatment with LPS. Moreover, unlike expression of Wnt5a, which was limited to macrophages and dendritic cells, stimulated lymphocytes also showed a 10-fold increase in expression of Frizzled-5 mRNA. In vivo studies showed the presence of Wnt5 mRNA and Frizzled-5 protein expression in granulomatous lesions isolated from pulmonary tuberculosis patients. This was an important finding since it demonstrates that Wnt5a and Frizzled-5 are expressed in the proper location (ie, the granuloma) to promote the host response to an M tuberculosis infection.
The crux of the study, however, is the functional link between Wnt5a/Frizzled-5 expression and macrophage and T-cell activation. The authors made the startling discovery that peripheral-blood mononuclear cells (PBMCs) isolated from healthy donors who were negative for "purified protein derivative of M tuberculosis" (PPD) were diminished in their production of PPD-induced IFN-
These exciting studies suggest a new order of complexity in regulating the bridge between the innate and acquired immune responses. Since pathogenic organisms including M tuberculosis release various factors that can modulate an immune response, one might predict that interfering with the production of Wnt5a, its interaction with Frizzled-5, or the downstream signaling from the receptor might be important mechanisms by which pathogens limit the acquired immune response. References
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
in the presence of neutralizing anti-Wnt5a antibody. This suggests that the antigen-induced release of this essential cytokine from T cells was dependent on the production of Wnt5a by antigen-presenting cells (APCs). A similar decrease in IFN-
