Growth Differentiation Factor-15 Orchestrates Inflammation-Related Diseases via Macrophage Polarization

Macrophage polarization is a critical determinant of disease progression and regression. Studies on macrophage plasticity and polarization can provide a theoretical basis for the tactics of diagnosis and treatment for macrophage-related diseases. These include inflammation-related diseases, such as sepsis, tumors, and metabolic disorders. Growth differentiation factor-15 (GDF-15) or macrophage inhibitory cytokine-1, a 25 kDa secreted homodimeric protein, is a member of the transforming growth factor-β (TGF-β) superfamily that is released in response to external stressors. GDF-15 regulates biological effects such as tumor occurrence, inflammatory response, tissue damage, angiogenesis, and bone metabolism. It has been shown to exert anti-inflammatory and pro-inflammatory effects in inflammation-related diseases. Moreover, inflammatory stimuli can induce GDF-15 expression in immune and parenchymal cells. GDF-15 exhibits a feedback inhibitory effect by inhibiting tumor necrosis factor-α secretion during the macrophage activation anaphase, suggesting that there may be a close association between the two. GDF-15 directly induces CD14⁺ monocytes to produce the M2-like macrophage phenotype, inhibits monocyte-derived macrophage for M1-like polarization, and induces monocyte-derived Mφ for M2-like polarization. This review summarizes the macrophage polarization mechanism of GDF-15 under the conditions of sepsis, colon cancer, atherosclerosis, and obesity. An improved understanding of the role and molecular mechanisms of action of GDF-15 could greatly elucidate the mechanism of disease occurrence and development and provide new ideas for targeted disease prevention and treatment. An advanced understanding of the function and molecular mechanisms of action of GDF-15 may be helpful in the assessment of its potential value as a therapeutic and diagnostic target.