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Article

Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Granulocyte Neutrophil

by
Alejandra Infante Cruz
1,†,
Paula María Saibene Vélez
1,2,†,
Cynthia Arasanz
1,3,
Micaela Rosato
1,2,
Federico Remes Lenicov
4,
Juan Iturrizaga
5,
Martín Abelleyro
1,
Marianela Candolfi
6,
Eleonora Regueira
7,
Gladys Hermida
7,
Mónica Vermeulen
1,8,
Silvia Berner
9,
Francisco José Barrantes
10,
Silvia de la Vega
11,
Carolina Jancic
1,8,
Marcela Solange Villaverde
12 and
Gabriela Verónica Salamone
1,8,*
1
Instituto de Medicina Experimental (IMEX–CONICET)–Academia Nacional de Medicina, Buenos Aires C1425AUM, Argentina
2
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
3
Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Instituto Universitario, Buenos Aires C1037ACA, Argentina
4
Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires–CONICET, Buenos Aires C1053ABH, Argentina
5
División Neurocirugía, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
6
Instituto de Investigaciones Biomédicas (INBIOMED UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
7
Laboratorio de Biología de Anfibios-Histología Animal, Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
8
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
9
Servicio de Neurocirugía de la Clínica y Maternidad Santa Isabel, Buenos Aires C1406DKG, Argentina
10
Molecular Neurobiology Division, BIOMED UCA-CONICET, Buenos Aires C1107AAZ, Argentina
11
Sección Anatomía Patológica del Hospital de Quemados “Arturo U. Illia” CABA, Buenos Aires C1424BSD, Argentina
12
Unidad de Transferencia Genética y Laboratorio de Metabolismo, Departamento de Biología, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, Área Investigación, Universidad de Buenos Aires, Buenos Aires C1053ABH, Argentina
 
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*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(1), 321; https://doi.org/10.3390/ijms27010321 (registering DOI)
Submission received: 17 September 2025 / Revised: 18 December 2025 / Accepted: 19 December 2025 / Published: 27 December 2025
(This article belongs to the Special Issue The Impact of the Immune System on the Tumor Microenvironment: Relevance to Glioma Development)
Review Reports Versions Notes

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression.
Keywords: acetylcholine; glioblastoma; neutrophils; M3 muscarinic acetylcholine receptor acetylcholine; glioblastoma; neutrophils; M3 muscarinic acetylcholine receptor

Share and Cite

MDPI and ACS Style

Cruz, A.I.; Vélez, P.M.S.; Arasanz, C.; Rosato, M.; Remes Lenicov, F.; Iturrizaga, J.; Abelleyro, M.; Candolfi, M.; Regueira, E.; Hermida, G.; et al. Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Granulocyte Neutrophil. Int. J. Mol. Sci. 2026, 27, 321. https://doi.org/10.3390/ijms27010321

AMA Style

Cruz AI, Vélez PMS, Arasanz C, Rosato M, Remes Lenicov F, Iturrizaga J, Abelleyro M, Candolfi M, Regueira E, Hermida G, et al. Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Granulocyte Neutrophil. International Journal of Molecular Sciences. 2026; 27(1):321. https://doi.org/10.3390/ijms27010321

Chicago/Turabian Style

Cruz, Alejandra Infante, Paula María Saibene Vélez, Cynthia Arasanz, Micaela Rosato, Federico Remes Lenicov, Juan Iturrizaga, Martín Abelleyro, Marianela Candolfi, Eleonora Regueira, Gladys Hermida, and et al. 2026. "Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Granulocyte Neutrophil" International Journal of Molecular Sciences 27, no. 1: 321. https://doi.org/10.3390/ijms27010321

APA Style

Cruz, A. I., Vélez, P. M. S., Arasanz, C., Rosato, M., Remes Lenicov, F., Iturrizaga, J., Abelleyro, M., Candolfi, M., Regueira, E., Hermida, G., Vermeulen, M., Berner, S., Barrantes, F. J., Vega, S. d. l., Jancic, C., Villaverde, M. S., & Salamone, G. V. (2026). Influence of the Cholinergic System on the Pathogenesis of Glioblastoma: Impact of the Granulocyte Neutrophil. International Journal of Molecular Sciences, 27(1), 321. https://doi.org/10.3390/ijms27010321

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