Reprogramming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation

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...

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Detalles Bibliográficos
Autores: 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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/390202
Acceso en línea:http://hdl.handle.net/10261/390202
Access Level:acceso abierto
Palabra clave:GSK3
human
immunology
inflammation
macrophage reprogramming
macrophages
Descripción
Sumario: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.

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