4.6 Article

Wnt5a-Rac1-NF-kB Homeostatic Circuitry Sustains Innate Immune Functions in Macrophages

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JOURNAL OF IMMUNOLOGY
卷 192, 期 9, 页码 4386-4397

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AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302817

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  1. Department of Biotechnology
  2. Government of India
  3. Council of Scientific and Industrial Research
  4. University Grants Commission (UGC)
  5. UGC-Dr. D. S. Kothari Fellowship

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Macrophages play a critical role in innate immunity. Differentiation Ags present on macrophages such as CD14 orchestrate the first line of defense against infection. The basal/homeostatic signaling scheme that keeps macrophages thus groomed for innate immune functions remains unresolved. Wnt5a-Fz5 signaling being a primordial event during cell differentiation, we examined the involvement of Wnt5a-Fz5 signaling in the maintenance of innate immune functions. In this study, we demonstrate that innate immune functions of macrophages ensue at least partly through a homeostatic Wnt5a-Fz5-NF-kB (p65) circuit, which is Rac1 dependent. The autocrine/paracrine Wnt5a-Fz5-Rac1-p65 signaling cascade not only maintains basal levels of the immune defense modulating IFNs and CD14; it also supports macrophage survival. Wnt5a-Fz5-Rac1 signaling mediated p65 homeostasis in turn sustains Wnt5a expression in a feed-forward mode. The natural immune response of macrophages to Escherichia coli/LPS and virus is accordingly sustained. The depiction of sustenance of innate immune functions as an outcome of a homeostatic Wnt5a-p65 axis unfolds previously unidentified details of immune regulation and provides new insight into homeostatic cell signaling.

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