PIF2025 - Macrophage re-programming through modulation of the GSK3/MAFB-MAF-dependent anti-inflammatory and pro-fibrotic profile - (PID2024-157082OB-I00)

Macrophages exhibit a huge functional plasticity and acquire pro- or anti-inflammatory, and pro- or anti-tumoral functions depending on their origin and the surrounding tissue microenvironment. The relevance of the shifts between macrophage functional states is illustrated by the pathological consequences of deregulated macrophage specialization, which leads to, or is associated with, chronic inflammatory pathologies like obesity, fibrosis, rheumatoid arthritis, atherosclerosis and cancer. Consequently, macrophage re-programming has emerged as a promising therapeutic approach for these chronic conditions. However, advancing macrophage-centered therapies requires a deeper understanding of the molecular mechanisms underlying their functional plasticity. The central hypothesis of this grant proposal is that modulation of the GSK3/MAFB-MAF network offers a promising and realistic therapeutic strategy for re-programming of human monocyte-derived macrophages. This hypothesis stems from previous findings by our group, which demonstrate that: 1) MAFB and MAF determine the anti-inflammatory nature of human macrophages; 2) GSK3 inhibition and MAFB/MAF expression are essential for the acquisition of the anti-inflammatory, reparative and immunosuppressive profiles of human macrophages; 3) blockade of GSK3 activity suffices to switch pro-inflammatory into anti-inflammatory macrophages; and 4) inhibition of GSK3 promotes the loss of the transcriptional profile of alveolar macropha