TY - JOUR
T1 - GSK3β Inhibition Prevents Macrophage Reprogramming by High-Dose Methotrexate
AU - Ríos, Israel
AU - López-Navarro, Baltasar
AU - Torres-Torresano, Mónica
AU - Soler Palacios, Blanca
AU - Simón-Fuentes, Miriam
AU - Domínguez-Soto, Ángeles
AU - Muller, Ittai B
AU - Jansen, Gerrit
AU - Corbí, Ángel L
AU - Puig-Kröger, Amaya
N1 - Funding Information: This work was supported by Grant PI17/00037 and PI20/00316 from Instituto de Salud Carlos III to A.P.K., Grant PID2020-114323RB-I00 from Ministerio de Ciencia e Innovación to A.L.C., “Ayudas FUNDACIÓN BBVA a equipos de investigación científica SARS-CoV-2 y COVID-19” to A.L.C., and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/0007), and cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF), to A.L.C. and A.P.K. This research work was funded by the European Commission-NextGenerationEU, through CSICs Global Health Platform (PTI Salud Global). This work was supported in part by a grant from the Dutch Society for Clinical Chemistry (NVKC) to I.B. Muller and R. de Jonge. M.S.F. was funded by a Formación de Personal Investigador predoctoral fellowship from Ministerio de Ciencia e Innovación (Grant PRE2018-083396). Publisher Copyright: © 2023 S. Karger AG. All rights reserved.
PY - 2023/11/14
Y1 - 2023/11/14
N2 - Methotrexate (MTX) is an antifolate drug used as a chemotherapeutic agent for acute lymphoblastic leukemia, where MTX improves patients' prognosis. Macrophage reprogramming is being increasingly assessed as an antitumor therapeutic strategy. However, and although MTX limits the pathogenic action of macrophages in chronic inflammatory diseases, its effects on tumor-promoting macrophages have not been previously explored. We now report that MTX shapes the transcriptional and functional profile of M-CSF-dependent human macrophages, whose transcriptome is highly enriched in the gene signature that defines pathogenic tumor-associated macrophages ("large TAM"). Specifically, MTX prompted the acquisition of the gene signature of antitumoral "small TAM" and skewed macrophages toward an IL-6high IFNβ1high IL-10low phenotype upon subsequent stimulation. Mechanistically, the MTX-induced macrophage reprogramming effect correlated with a reduction of the M-CSF receptor CSF1R expression and function, as well as a diminished expression of MAF and MAFB transcription factors, primary determinants of pro-tumoral macrophages whose transcriptional activity is dependent on GSK3β. Indeed, the ability of MTX to transcriptionally reprogram macrophages toward an antitumoral phenotype was abrogated by inhibition of GSK3β. Globally, our results establish MTX as a macrophage reprogramming drug and indicate that its ability to modulate macrophage polarization may also underlie its therapeutic benefits. Since GSK3β inhibition abrogates the reprogramming action of MTX, our results suggest that the GSK3β-MAFB/MAF axis constitutes a target for the macrophage-centered antitumor strategies.
AB - Methotrexate (MTX) is an antifolate drug used as a chemotherapeutic agent for acute lymphoblastic leukemia, where MTX improves patients' prognosis. Macrophage reprogramming is being increasingly assessed as an antitumor therapeutic strategy. However, and although MTX limits the pathogenic action of macrophages in chronic inflammatory diseases, its effects on tumor-promoting macrophages have not been previously explored. We now report that MTX shapes the transcriptional and functional profile of M-CSF-dependent human macrophages, whose transcriptome is highly enriched in the gene signature that defines pathogenic tumor-associated macrophages ("large TAM"). Specifically, MTX prompted the acquisition of the gene signature of antitumoral "small TAM" and skewed macrophages toward an IL-6high IFNβ1high IL-10low phenotype upon subsequent stimulation. Mechanistically, the MTX-induced macrophage reprogramming effect correlated with a reduction of the M-CSF receptor CSF1R expression and function, as well as a diminished expression of MAF and MAFB transcription factors, primary determinants of pro-tumoral macrophages whose transcriptional activity is dependent on GSK3β. Indeed, the ability of MTX to transcriptionally reprogram macrophages toward an antitumoral phenotype was abrogated by inhibition of GSK3β. Globally, our results establish MTX as a macrophage reprogramming drug and indicate that its ability to modulate macrophage polarization may also underlie its therapeutic benefits. Since GSK3β inhibition abrogates the reprogramming action of MTX, our results suggest that the GSK3β-MAFB/MAF axis constitutes a target for the macrophage-centered antitumor strategies.
KW - Macrophage reprogramming
KW - Macrophages
KW - Methotrexate
UR - http://www.scopus.com/inward/record.url?scp=85160515814&partnerID=8YFLogxK
U2 - https://doi.org/10.1159/000526622
DO - https://doi.org/10.1159/000526622
M3 - Article
C2 - 36380627
SN - 1662-811X
VL - 15
SP - 283
EP - 296
JO - Journal of innate immunity
JF - Journal of innate immunity
IS - 1
ER -