Ríos Israel, Herrero Cristina, Torres-Torresano Mónica, López-Navarro Baltasar, Schiaffino María Teresa, Díaz Crespo Francisco, Nieto-Valle Alicia, Samaniego Rafael, Sierra-Palomares Yolanda, Oliver Eduardo, Revuelta-Salgado Fernando, García-Luján Ricardo, Sánchez-Mateos Paloma, Delgado Rafael, Puig-Kröger Amaya, Corbí Angel L
Myeloid Cell Laboratory, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Laboratorio de Inmuno-Metabolismo e Inflamación, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Elife. 2025 May 14;14:RP102659. doi: 10.7554/eLife.102659.
Monocyte-derived macrophages recruited into inflamed tissues can acquire an array of functional states depending on the extracellular environment. Since the anti-inflammatory/pro-fibrotic macrophage profile is determined by MAFB, whose activity/protein levels are regulated by GSK3, we addressed the macrophage reprogramming potential of GSK3 modulation. GM-CSF-dependent (GM-MØ) and M-CSF-dependent monocyte-derived macrophages (M-MØ) exhibited distinct levels of inactive GSK3, and inhibiting GSK3 in GM-MØ led to the acquisition of transcriptional, phenotypic, and functional properties characteristic of M-MØ (enhanced expression of IL-10 and monocyte-recruiting factors, and higher efferocytosis). These reprogramming effects were also observed upon GSK3α/β knockdown and through GSK3 inhibition in ex vivo isolated human alveolar macrophages (AMØ). Notably, GSK3 downmodulation potentiated the transcriptional signature of interstitial macrophages (IMØ) while suppressing the AMØ-specific gene profile. Indeed, heightened levels of inactive GSK3 and MAFB-dependent proteins were observed in severe COVID-19 patients' lung macrophages, highlighting the GSK3-MAFB axis as a therapeutic target for macrophage reprogramming.
募集到炎症组织中的单核细胞衍生巨噬细胞可根据细胞外环境获得一系列功能状态。由于抗炎/促纤维化巨噬细胞表型由MAFB决定，而MAFB的活性/蛋白质水平受GSK3调控，我们研究了GSK3调节对巨噬细胞重编程的潜在作用。粒细胞-巨噬细胞集落刺激因子依赖型（GM-MØ）和巨噬细胞集落刺激因子依赖型单核细胞衍生巨噬细胞（M-MØ）表现出不同水平的无活性GSK3，在GM-MØ中抑制GSK3会导致其获得M-MØ特有的转录、表型和功能特性（IL-10和单核细胞募集因子表达增强，以及更高的吞噬作用）。在GSK3α/β敲低以及对体外分离的人肺泡巨噬细胞（AMØ）进行GSK3抑制时也观察到了这些重编程效应。值得注意的是，GSK3下调增强了间质巨噬细胞（IMØ）的转录特征，同时抑制了AMØ特异性基因谱。事实上，在重症COVID-19患者的肺巨噬细胞中观察到无活性GSK3和MAFB依赖蛋白水平升高，突出了GSK3-MAFB轴作为巨噬细胞重编程的治疗靶点。
