Abstract
Macrophages play pivotal roles in host defense and immune homeostasis, which have two major functional polarization states, the classically activated M1 and the alternatively activated M2. Interleukin (IL)-17A is an immune modulator able to shape macrophage phenotypes. Wnt/β-catenin is a developmental signaling pathway that plays crucial roles in morphogenesis and tissue homeostasis, which has also been recently demonstrated playing roles in immune regulation. A growing amount of evidence suggests that both Wnt and IL-17A signaling are involved in macrophage polarization. However, their interaction in macrophage polarization remains elusive. The aim of present study was to explore impacts of Wnt/β-catenin on IL-17A-mediated macrophage M1/M2 polarization in murine monocyte/macrophage-like cell line RAW264.7. Results revealed that IL-17A activated Wnt/β-catenin signaling and induced macrophage M1 polarization, but inhibited M2 polarization. In contrast, the activation of Wnt/β-catenin signaling led to the inhibition of M1 macrophage polarization but the promotion of M2 polarization. Importantly, the activation of Wnt/β-catenin also showed abilities to inhibit the IL-17A-induced M1 macrophage polarization while diminishing the IL-17A-inhibited M2 polarization. Molecular analysis further uncovered that the JAK/STAT signaling pathway was involved in the interaction of Wnt/β-catenin and IL-17A in the modulation of macrophage polarization. These results suggested that the Wnt/β-catenin signaling modulated IL-17A-altered macrophage polarization in part by regulating the JAK/STAT signaling pathway. This study thus revealed a novel function of Wnt/β-catenin signaling in regulating IL-17A-altered macrophage polarization.
Highlights
Macrophages are immune cells that play key roles in inflammatory and maintenance of immune homeostasis
An enhanced activation of Wnt/b-catenin signaling was observed in RAW264.7 cells treated with rhIL-17A, as determined by the expression of active b-catenin and target genes of Wnt/b-catenin signaling, and the rhIL-17A-triggered Wnt signaling activity could be diminished by XAV939 (Po0.01)
B and C, Semiquantitative analysis of the expression of proteins in (A) showing fold-changes of Arg1 and inducible nitric oxide synthase (iNOS) in cells treated with Wnt3a-conditional medium (CM) and/or XAV939 with or without rhIL-17A as determined by densitometry assay using ImageJ software Fiji
Summary
Macrophages are immune cells that play key roles in inflammatory and maintenance of immune homeostasis. In this regard, macrophages are able to eradicate a variety of pathogenic microorganisms by phagocytosis in the body [1], where they are implicated in the regulation of inflammatory occurrence and development by producing pro-inflammatory/anti-inflammatory factors in response to an infection and/or insult stress [2]. M1 macrophages are characterized as a classic activated macrophage phenotype They are typically polarized by Th1 cytokines such as interferon-g or lipopolysaccharide, and initiate an immune response by producing pro-inflammatory cytokines, reactive oxygen intermediates, and nitric oxide, phagocytizing microbes. An excessive activation of M1 macrophages may cause damage and disturbances of homeostasis in their resident tissues [5]
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