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

Jia,Jing; Zhang,Haibao; He,Lin; Zhang,Hongke; Shu,Maoguo

doi:10.3892/or.2020.7513

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

Authors:
- Jing Jia
- Haibao Zhang
- Lin He
- Hongke Zhang
- Maoguo Shu
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Affiliations: Department of Plastic, Cosmetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
Published online on: February 21, 2020 https://doi.org/10.3892/or.2020.7513
Pages: 1319-1330

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Abstract

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.

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1	Serra E, Puig S, Otero D, Gaona A, Kruyer H, Ars E, Estivill X and Lázaro C: Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Am J Hum Genet. 61:512–519. 1997. View Article : Google Scholar : PubMed/NCBI
2	Granström S, Langenbruch A, Augustin M and Mautner VF: Psychological burden in adult neurofibromatosis type 1 patients: Impact of disease visibility on body image. Dermatology. 224:160–167. 2012. View Article : Google Scholar : PubMed/NCBI
3	Riccardi VM: Ketotifen suppression of NF1 neurofibroma growth over 30 years. Am J Med Genet A. 167:1570–1577. 2015. View Article : Google Scholar : PubMed/NCBI
4	Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL and Johnson KJ: Neurofibromatosis type 1. Nat Rev Dis Primers. 3:170042017. View Article : Google Scholar : PubMed/NCBI
5	Zhu Y, Ghosh P, Charnay P, Burns DK and Parada LF: Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science. 296:920–922. 2002. View Article : Google Scholar : PubMed/NCBI
6	Demestre M, Herzberg J, Holtkamp N, Hagel C, Reuss D, Friedrich RE, Kluwe L, Von Deimling A, Mautner VF and Kurtz A: Imatinib mesylate (Glivec) inhibits Schwann cell viability and reduces the size of human plexiform neurofibroma in a xenograft model. J Neurooncol. 98:11–19. 2010. View Article : Google Scholar : PubMed/NCBI
7	Takata M, Imai T and Hirone T: Factor-XIIIa-positive cells in normal peripheral nerves and cutaneous neurofibromas of type-1 neurofibromatosis. Am J Dermatopathol. 16:37–43. 1994. View Article : Google Scholar : PubMed/NCBI
8	Park SJ, Sawitzki B, Kluwe L, Mautner VF, Holtkamp N and Kurtz A: Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Med. 11:1092013. View Article : Google Scholar : PubMed/NCBI
9	Rizvi TA, Huang Y, Sidani A, Atit R, Largaespada DA, Boissy RE and Ratner N: A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. J Neurosci. 22:9831–9840. 2002. View Article : Google Scholar : PubMed/NCBI
10	Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, et al: Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 125:159–168. 2013. View Article : Google Scholar : PubMed/NCBI
11	Donovan S, Shannon KM and Bollag G: GTPase activating proteins: Critical regulators of intracellular signaling. Biochim Biophys Acta. 1602:23–45. 2002.PubMed/NCBI
12	Dineen SP, Lynn KD, Holloway SE, Miller AF, Sullivan JP, Shames DS, Beck AW, Barnett CC, Fleming JB and Brekken RA: Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 68:4340–4346. 2008. View Article : Google Scholar : PubMed/NCBI
13	Keepers TR, Gross LK and Obrig TG: Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic-uremic syndrome. Infect Immun. 75:1229–1236. 2007. View Article : Google Scholar : PubMed/NCBI
14	Chen Z, Mo J, Brosseau JP, Shipman T, Wang Y, Liao CP, Cooper JM, Allaway RJ, Gosline SJC, Guinney J, et al: Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway. Cancer Discov. 9:114–129. 2019. View Article : Google Scholar : PubMed/NCBI
15	Rawat SJ, Araiza-Olivera D, Arias-Romero LE, Villamar-Cruz O, Prudnikova TY, Roder H and Chernoff J: H-ras inhibits the hippo pathway by promoting Mst1/Mst2 heterodimerization. Curr Biol. 26:1556–1563. 2016. View Article : Google Scholar : PubMed/NCBI
16	Kwon Y, Vinayagam A, Sun X, Dephoure N, Gygi SP, Hong P and Perrimon N: The Hippo signaling pathway interactome. Science. 342:737–740. 2013. View Article : Google Scholar : PubMed/NCBI
17	Gérard C and Goldbeter A: The balance between cell cycle arrest and cell proliferation: Control by the extracellular matrix and by contact inhibition. Interface Focus. 4:201300752014. View Article : Google Scholar : PubMed/NCBI
18	Murakami S, Shahbazian D, Surana R, Zhang W, Chen H, Graham GT, White SM, Weiner LM and Yi C: Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma. Oncogene. 36:1232–1244. 2017. View Article : Google Scholar : PubMed/NCBI
19	Kim W, Khan SK, Liu Y, Xu R, Park O, He Y, Cha B, Gao B and Yang Y: Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut. 67:1692–1703. 2018. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Shi GP and Lindholt JS: Mast cells in abdominal aortic aneurysms. Curr Vasc Pharmacol. 11:314–326. 2013. View Article : Google Scholar : PubMed/NCBI
22	Brosseau JP, Pichard DC, Legius EH, Wolkenstein P, Lavker RM, Blakeley JO, Riccardi VM, Verma SK, Brownell I and Le LQ: The biology of cutaneous neurofibromas: Consensus recommendations for setting research priorities. Neurology. 91((2 Suppl 1)): S14–S20. 2018. View Article : Google Scholar : PubMed/NCBI
23	Choi K, Komurov K, Fletcher JS, Jousma E, Cancelas JA, Wu J and Ratner N: An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Sci Rep. 7:433152017. View Article : Google Scholar : PubMed/NCBI
24	Müller M, Wacker K, Getts D, Ringelstein EB and Kiefer R: Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide-induced neuropathy. Glia. 56:1005–1016. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ribeiro S, Napoli I, White IJ, Parrinello S, Flanagan AM, Suter U, Parada LF and Lloyd AC: Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep. 5:126–136. 2013. View Article : Google Scholar : PubMed/NCBI
26	Nguyen R, Ibrahim C, Friedrich RE, Westphal M, Schuhmann M and Mautner VF: Growth behavior of plexiform neurofibromas after surgery. Genet Med. 15:691–697. 2013. View Article : Google Scholar : PubMed/NCBI
27	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI
28	Geller M, Ribeiro MG, Araújo AP, de Oliveira LJ and Nunes FP: Serum IgE levels in neurofibromatosis 1. Int J Immunogenet. 33:111–115. 2006. View Article : Google Scholar : PubMed/NCBI
29	Kamide R, Nomura N and Niimura M: Characterization of mast cells residing in cutaneous neurofibromas. Dermatologica. 179 (Suppl 1):S1241989. View Article : Google Scholar
30	Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA and Ratner N: Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell. 13:105–116. 2008. View Article : Google Scholar : PubMed/NCBI
31	Evans DG: Neurofibromatosis type 2 (NF2): A clinical and molecular review. Orphanet J Rare Dis. 4:162009. View Article : Google Scholar : PubMed/NCBI
32	Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X, Ji X, Ji F, Gong XG, Li L, et al: Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 31:247–259. 2017. View Article : Google Scholar : PubMed/NCBI
33	Brauß TF, Winslow S, Lampe S, Scholz A, Weigert A, Dehne N, von Stedingk K, Schmid T and Brüne B: The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors. Mol Carcinog. 56:2620–2629. 2017. View Article : Google Scholar : PubMed/NCBI
34	Qin S, Zheng JH, Xia ZH, Qian J, Deng CL and Yang SL: CTHRC1 promotes wound repair by increasing M2 macrophages via regulating the TGF-β and notch pathways. Biomed Pharmacother. 113:1085942019. View Article : Google Scholar : PubMed/NCBI