Transforming Growth Factor-β1 Signaling in Macrophages: From MAD/SMAD Homology to Diabetic Complications

ABSTRACT: Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that plays pivotal but often opposing roles in immune regulation and tissue homeostasis. In macrophages, TGF-β1 signaling integrates inflammatory, metabolic, and fibrotic responses in a highly context-dependent manner. This review comprehensively investigates TGF-β1 signaling mechanisms, metabolic crosstalk, and clinical significance in macrophages, with a focus on diabetic complications. The canonical SMAD2/3-dependent pathway, together with alternative SMAD1/5-dependent signaling and non-SMAD routes (including mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling), enables signaling divergence that allows TGF-β1 to exert both anti-inflammatory and profibrotic effects. Pioneering work established the core mechanistic framework, while other studies elucidated its role in alternative macrophage activation and tissue remodeling. Recent investigations associate high-glucose culture conditions with increased lactate and altered TGF-β1/SMAD1/5 signaling in human macrophages, suggesting a link between metabolic reprogramming and pro-atherogenic programs. In diabetes, chronic hyperglycemia can reprogram macrophages and alter their responses to TGF-β1, potentially sustaining inflammation and fibrosis. These macrophage responses are discussed in relation to diabetic kidney disease, retinopathy, neuropathy, cardiomyopathy, and impaired wound healing. The glucose–lactate–TGF-β1/SMAD1/5 sequence remains a candidate mechanism: lactate mediation, osmotic effects, and consequent organ injury have not been resolved. Therapeutic targeting of TGF-β1 remains challenging because of its dualistic nature, which requires context-specific modulation and direct assessment of repair and safety. This review discusses emerging strategies, including macrophage-targeted approaches and combined immunometabolic interventions. A deeper understanding of context-dependent TGF-β1 signaling in macrophages is essential for developing precision therapies that mitigate diabetic complications while preserving physiological immune and reparative functions.