Wnt-3a Induces Cytokine Release in Human Mast Cells

Julia Tebroke,Gunnar Schulte,Gunnar Nilsson,Joris E Lieverse,Jesper Säfholm,Elin Rönnberg

doi:10.3390/cells8111372

Julia Tebroke, Gunnar Schulte + Show 4 more

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https://doi.org/10.3390/cells8111372

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Abstract

Mast cells are well known for their detrimental effects in allergies and asthma, and Wnt signaling has recently been implicated in asthma and other airway diseases. However, it is not known if or how Wnts affect human mast cells. Since Wnt expression is elevated in individuals with asthma and is linked to a Th2 profile, we hypothesized that mast cells could be affected by Wnts in the context of asthma. We therefore sought to investigate the role of Wnt signaling in human mast cell development and activation. We first examined the expression of the 10 main Wnt receptors, Frizzled 1–10 (FZD1–10), and found expression of several FZDs in human mast cells. Treatment with purified recombinant Wnt-3a or Wnt-5a did not affect the proliferation or maturation of CD34+ progenitors into mast cells, as indicated by cellular expression of CD117 and FcεRI, activation by FcεRI crosslinking, and histamine and tryptase release. Furthermore, Wnt treatment did not change the phenotype from MCT to MCTC, since MrgX2 expression, compound 48/80-mediated activation, and carboxypeptidase A3 content were not affected. However, Wnt-3a activated WNT/β-catenin signaling in mature human mast cells, as revealed by stabilization of β-catenin, upregulation of IL-8 and CCL8 mRNA expression, and release of IL-8 protein. Thus, our data suggest that Wnt-3a activation of mast cells could contribute to the recruitment of immune cells in conditions associated with increased Wnt-3a expression, such as asthma.

Highlights

Mast cells are important for surveillance of and responses to pathogens and cell injury but can be detrimental to the host in the contexts of allergies, anaphylaxis, asthma, and other hypersensitivity reactions [1]
The Wnt lipoglycoproteins form a family of 19 secreted ligands that are recognized by 10 Frizzled receptors (FZD1–10 ), G protein-coupled receptors that associate with various coreceptors [5]
Wnt ligands and their receptors participate in numerous possible ligand/receptor/coreceptor interactions and signal through different downstream pathways, which have been divided into three branches; these branches include the β-catenin-dependent or WNT/β-catenin pathway and an additional network of β-catenin-independent pathways, such as planar cell polarity (PCP)-like signaling pathways and G protein-dependent signaling pathways [5,6]

Summary

Introduction

Mast cells are important for surveillance of and responses to pathogens and cell injury but can be detrimental to the host in the contexts of allergies, anaphylaxis, asthma, and other hypersensitivity reactions [1] These cells are widely distributed in the body and are numerous in areas exposed to the external environment, such as the lungs, skin, and gastrointestinal tract [1,2]. The Wnt lipoglycoproteins form a family of 19 secreted ligands that are recognized by 10 Frizzled receptors (FZD1–10 ), G protein-coupled receptors that associate with various coreceptors [5] Wnt ligands and their receptors participate in numerous possible ligand/receptor/coreceptor interactions and signal through different downstream pathways, which have been divided into three branches; these branches include the β-catenin-dependent or WNT/β-catenin pathway and an additional network of β-catenin-independent pathways, such as planar cell polarity (PCP)-like signaling pathways and G protein-dependent signaling pathways [5,6]. Multiple Wnt genes (e.g., WNT3A, WNT5a, WNT6, and WNT10A) and the receptor FZD5 are positively correlated to a Th2 signature in the airways of humans with asthma [9]

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