Cutaneous neurofibroma cells with active YAP promotes proliferation of macrophages resulting in increased accumulation of macrophages by modulating CCL5 and TGF‑β1

Cutaneous neurofibromas (cNFs) are present in the majority of patients with neurofibromatosis type 1 (NF1), and results in disfigurements of the body, which is associated with psychological distress. A hallmark feature of cNF is the infiltration of inflammatory cells, among which macrophages are an important component of the microenvironment. Loss of neurofibromin (Nf1) expression results in activation of the PI3K and MAPK signaling pathways; however, the therapeutic effects of specific inhibitors targeting these pathways are not satisfactory. The present study showed increased macrophage infiltration accompanied by activation of effectors of the Hippo signaling pathway. Additionally, it was shown that XMU‑MP‑1 enhanced macrophage accumulation, in vivo and in vitro, by elevating the levels of C‑C motif chemokine ligand 5 (CCL5) and transforming growth factor (TGF)‑β1 expression. However, neither CCL5 nor TGF‑β1 ablation alone were able to effectively reverse the XMU-MP-1-induced upregulation of macrophage accumulation, whereas concurrent ablation of these two genes significantly decreased macrophage accumulation. EdU staining and flow cytometry suggested that activated Yes‑associated protein 1 promoted proliferation rather than inhibiting apoptosis in macrophage cells, and this may underlie the increase in the accumulation of macrophages. Both CCL5/C‑C motif chemokine receptor 5 and TGF-β1/TGFβ1 receptor served crucial roles in modulating macrophage proliferation, which ultimately contributed to macrophage accumulation. The function of the Hippo pathway in the development of cNF development and its potency as a therapeutic target merit further investigation.