Barik Susmita, Goswami Sanghamitra, Nanda Prakash Kumar, Sarkar Argajit, Saha Bhaskar, Sarkar Arup, Bhattacharjee Surajit
Trident Academy of Creative Technology, Bhubaneswar, Odisha, India.
Department of Molecular Biology and Bioinformatics, Tripura University, Agartala, India.
Cytokine. 2025 Mar;187:156865. doi: 10.1016/j.cyto.2025.156865. Epub 2025 Jan 27.
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.
转化生长因子-β（TGF-β）在免疫抑制和发病机制中发挥双重作用，已成为抗利什曼原虫免疫反应的关键调节因子。在利什曼原虫感染中，TGF-β通过增强调节性T细胞（T-reg）分化和抑制巨噬细胞活化来驱动免疫偏离，从而抑制关键的抗寄生虫反应。这种细胞因子同时促进感染组织中的成纤维细胞增殖、细胞外基质产生和纤维化，这有助于伤口愈合，但会阻碍免疫细胞浸润，尤其是在内脏利什曼病中，脾脏结构紊乱和免疫通路受损较为明显。与白细胞介素-6一起，TGF-β调节致病性Th17反应，加剧炎症损伤并破坏组织结构。虽然TGF-β的免疫抑制作用使寄生虫得以持续存在，但其在维持组织完整性方面的作用带来了治疗潜力。通过TGF-β受体或信号中间体的选择性抑制剂对TGF-β信号进行靶向调节，有可能增强寄生虫清除率，同时将免疫病理学降至最低。实验研究表明，阶段特异性干预策略可能允许进行可控的免疫刺激或减少纤维化，增强宿主抵抗力而不引起炎症损伤。本综述讨论了TGF-β在利什曼病中协调免疫偏离、纤维化和发病机制的复杂作用，提出了选择性调节TGF-β途径以恢复宿主免疫力的新治疗途径。
