Activation of PLCγ/AKT/IκBα/p65 signaling increases inflammation in mast cells to promote growth of cutaneous neurofibroma

Abstract

Aim: Cutaneous neurofibroma (cNF), a hallmark feature of neurofibromatosis type 1 (NF1), results in psychological and physical damage to patients. Considering the important role of mast cells in neurofibroma development, the aim of this study was to elucidate the underlying mechanism of the interaction between cNF cells and mast cells.

Main methods: SW10 cells with Nf1 knocked down were used as a cNF cell model. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays, as well as a mouse xenograft tumor model, were used to assess the cNF tumor growth in vivo and in vitro. ELISAs and IHC were used to examine the inflammatory activity of mast cells.

Key findings: We demonstrated that cNF cells activated mast cells, which in turn promoted the cNF cell growth, while suppression of the inflammatory activity of cNF-associated mast cells reversed their stimulating effect on the growth of cNF cells. Mechanistic studies revealed that SW10 cells upregulated PLCγ/AKT/IκBα/p65 signaling in mast cells, thereby increasing inflammation. Moreover, PLCγ modulated the AKT/IκBα/p65 signaling activity and played a critical role in the interaction of mast cells and cNF cells. Knockdown of PLCγ in mast cells diminished their cNF cell-induced inflammatory activity and subsequently reduced the cNF cell growth in vivo and in vitro.

Significance: This study revealed a novel interaction between mast cells and cNF cells, suggesting a potential strategy for treating cNF by targeting the newly recognized signaling pathway.

Keywords: AKT/IκBα/p65 signaling; Cutaneous neurofibroma; Inflammatory activity; Mast cell; PLCγ.