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bioRxiv · 10.1101/2024.08.20.608749

Re-programming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation

Rios, I.·Herrero, C.·Torres Torresano, M.·Lopez-Navarro, B.·Schiaffino, M. T.·Diaz Crespo, F.·Nieto-Valle, A.·Samaniego, R.·Sierra-Palomares, Y.·Oliver, E.·Revuelta, F.·Garcia-Lujan, R.·Sanchez-Mateos, P.·Delgado, R.·Puig-Kroger, A.·Corbi, A. L.
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Abstract

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 re-programming potential of GSK3 modulation. GM-CSF-dependent (GM-MO) and M-CSF-dependent monocyte-derived macrophages (M-MO) exhibited distinct levels of inactive GSK3, and inhibiting GSK3 in GM-MO led to acquisition of transcriptional, phenotypic and functional properties characteristic of M-MO (enhanced expression of IL-10 and monocyte-recruiting factors, and higher efferocytosis). These re-programming effects were also observed upon GSK3/{beta} knockdown, and through GSK3 inhibition in ex vivo isolated human alveolar macrophages (AMO). Notably, GSK3 downmodulation potentiated the transcriptional signature of Interstitial Macrophages (IMO) while suppressed the AMO-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 re-programming.

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Rios, I., Herrero, C., Torres Torresano, M., Lopez-Navarro, B., Schiaffino, M. T., Diaz Crespo, F., Nieto-Valle, A., Samaniego, R., Sierra-Palomares, Y., Oliver, E., Revuelta, F., Garcia-Lujan, R., Sanchez-Mateos, P., Delgado, R., Puig-Kroger, A., Corbi, A. L.. 2024-08-20. Re-programming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation. https://doi.org/10.1101/2024.08.20.608749

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