Bento Carolina Adriane, Arnaud-Sampaio Vanessa Fernandes, Glaser Talita, Adinolfi Elena, Coutinho-Silva Robson, Ulrich Henning, Lameu Claudiana
Metastasis Molecular Mechanisms Laboratory and Neurosciences Laboratory, Institute of Chemistry, Biochemistry Department, University of Sao Paulo, Sao Paulo, Brazil.
Section of General Pathology, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy.
Purinergic Signal. 2025 Feb;21(1):51-68. doi: 10.1007/s11302-024-10051-w. Epub 2024 Oct 19.
Tumor-associated macrophages (TAMs) exhibit antitumor or protumor responses related to inflammatory (or M1) and alternative (or M2) phenotypes, respectively. The P2X7 receptor plays a key role in macrophage polarization, influencing inflammation and immunosuppression. In this study, we investigated the role of the P2X7 receptor in TAMs. Using P2X7 receptor-deficient macrophages, we analyzed gene expression profiles and their implications for neuroblastoma invasion and chemoresistance. Our results showed that P2X7 receptor deficiency altered the expression of classical polarization markers, such as nitric oxide synthase 2 (Nos2) and tumor necrosis factor-α (Tnf), as well as alternative phenotype markers, including mannose receptor C-type 1 (Mrc1) and arginase 1 (Arg1). P2X7 deficiency also influenced the expression of the ectonucleotidases Entpd1 and Nt5e and other purinergic receptors, especially P2ry2, suggesting compensatory mechanisms involved in macrophage polarization. In particular, TAMs deficient in P2X7 showed a phenotype with characteristics intermideiate between resting macrophages (M0) and M1 polarization rather than the M2-type phenotype like and wild-type TAM macrophages. In addition, P2rx7 TAMs regulated the expression of P2X7 receptor isoforms in neuroblastoma cells, with downregulation of the P2X7 A and B isoforms leading to a decrease in chemotherapy-induced cell death. However, TAMs expressing P2X7 downregulated only the B isoform, suggesting that TAMs play a role in modulating tumor behavior through P2X7 receptor isoform regulation. Taken together, our data underscore the regulatory function of the P2X7 receptor in orchestrating alternative macrophage polarization and in the interplay between tumor cells and TAMs. These findings help to clarify the complex interplay of purinergic signaling in cancer progression and open up avenues for future research and therapeutic interventions.
肿瘤相关巨噬细胞（TAM）分别表现出与炎症（或M1）和替代（或M2）表型相关的抗肿瘤或促肿瘤反应。P2X7受体在巨噬细胞极化中起关键作用，影响炎症和免疫抑制。在本研究中，我们调查了P2X7受体在TAM中的作用。使用P2X7受体缺陷型巨噬细胞，我们分析了基因表达谱及其对神经母细胞瘤侵袭和化疗耐药性的影响。我们的结果表明，P2X7受体缺陷改变了经典极化标志物如一氧化氮合酶2（Nos2）和肿瘤坏死因子-α（Tnf）的表达，以及替代表型标志物，包括甘露糖受体C型1（Mrc1）和精氨酸酶1（Arg1）。P2X7缺陷还影响了外核苷酸酶Entpd1和Nt5e以及其他嘌呤能受体的表达，尤其是P2ry2，提示巨噬细胞极化存在补偿机制。特别是，缺乏P2X7的TAM表现出一种介于静息巨噬细胞（M0）和M1极化之间的表型特征，而不是像野生型TAM巨噬细胞那样的M2型表型。此外，P2rx7 TAM调节神经母细胞瘤细胞中P2X7受体亚型的表达，P2X7 A和B亚型的下调导致化疗诱导的细胞死亡减少。然而，表达P2X7的TAM仅下调B亚型，表明TAM通过P2X7受体亚型调节在调节肿瘤行为中发挥作用。综上所述，我们的数据强调了P2X7受体在协调替代巨噬细胞极化以及肿瘤细胞与TAM之间相互作用中的调节功能。这些发现有助于阐明嘌呤能信号在癌症进展中的复杂相互作用，并为未来的研究和治疗干预开辟途径。
