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

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Macrophages adopt diverse functional states in response to tissue environments.
• The transcription factor MAFB influences anti-inflammatory and pro-fibrotic macrophage profiles.
• Glycogen synthase kinase 3 (GSK3) regulates MAFB activity and protein levels.

Purpose of the Study:

• To investigate the potential of modulating GSK3 to reprogram macrophage function.
• To determine if GSK3 inhibition can induce an anti-inflammatory/pro-fibrotic macrophage phenotype.

Main Methods:

• Compared GM-CSF-dependent (GM-MØ) and M-CSF-dependent (M-MØ) macrophages.
• Inhibited GSK3 in GM-MØ and ex vivo human alveolar macrophages (AMØ).
• Utilized GSK3α/β knockdown and chemical inhibition.

Main Results:

• GSK3 inhibition in GM-MØ induced M-MØ-like properties, including IL-10 and monocyte-recruiting factor expression, and enhanced efferocytosis.
• GSK3 modulation shifted macrophage profiles, potentiating interstitial macrophage (IMØ) signatures while suppressing alveolar macrophage (AMØ) genes.
• Elevated inactive GSK3 and MAFB-dependent proteins were found in lung macrophages from severe COVID-19 patients.

Conclusions:

• GSK3 inhibition effectively reprograms macrophages towards an anti-inflammatory/pro-fibrotic phenotype.
• The GSK3-MAFB axis represents a promising therapeutic target for macrophage reprogramming in inflammatory diseases.
• Dysregulated GSK3 and MAFB signaling in lung macrophages may contribute to severe COVID-19 pathology.