TGF-beta plays dual roles in immunity and pathogenesis in leishmaniasis

Transforming growth factor-beta (TGF-β), displaying a dual role in immunosuppression and pathogenesis, has emerged as a key regulator of anti-leishmanial immune responses. In Leishmania infections, TGF-β drives immune deviation by enhancing regulatory T-cell (T-reg) differentiation and inhibiting macrophage activation, suppressing critical antiparasitic responses. This cytokine simultaneously promotes fibroblast proliferation, extracellular matrix production, and fibrosis in infected tissues, which aids in wound healing but impedes immune cell infiltration, particularly in visceral leishmaniasis, where splenic disorganization and compromised immune access are notable. In conjunction with IL-6, TGF-β modulates pathogenic Th17 responses which intensify inflammatory damage and disrupt tissue architecture. While TGF-β's immunosuppressive actions enable parasite persistence, its role in maintaining tissue integrity introduces therapeutic potential. Targeted modulation of TGF-β signaling, through selective inhibitors of TGF-β receptors or signaling intermediates, has the potential to enhance parasite clearance while minimizing immunopathology. Experimental studies suggest that phase-specific intervention strategies may allow for controlled immunostimulation or fibrosis reduction, enhancing host resistance without incurring inflammatory injury. This review discusses the intricate role of TGF-β in orchestrating immune deviation, fibrosis, and pathogenesis in leishmaniasis, proposing novel therapeutic avenues for selective modulation of TGF-β pathways to restore host immunity.