Bioactive Lipid Signaling and Lipidomics in Macrophage Polarization: Impact on Inflammation and Immune Regulation

Juan P Rodríguez ¹ Javier Casas ² María A Balboa ³ Jesús Balsinde ^3*

• ¹ CONICET Instituto de Química Básica y Aplicada del Nordeste Argentino (IQUIBA), Corrientes, Corrientes, Argentina
• ² University of Valladolid, Valladolid, Spain
• ³ Instituto de Biología y Genética Molecular, CSIC,, Valladolid, Spain

Macrophages, crucial innate immune cells, defend against pathogens and resolve inflammation, maintaining tissue balance. They perform phagocytosis, present antigens to T cells, and bond innate and adaptive immunity through various activation states. Classical activation is associated with Th1 responses and interferon γ production, while alternative activation, induced by interleukin 4, is characterized by increased endocytosis, reduced secretion of pro-inflammatory cytokines, and roles in immunoregulation and tissue remodeling. Although these represent opposite extremes observed in vitro, the remarkable plasticity of macrophages allows for a wide spectrum of activation phenotypes that are complex to characterize experimentally. While the application of omics techniques has resulted in significant advances in the characterization of macrophage polarization, lipidomic studies have received lesser attention. Beyond their role as structural components and energy sources, lipids function as signaling molecules that regulate macrophage activation and polarization, thereby shaping immune responses. This work reviews the interaction between lipid signaling and macrophage polarization, exploring how lipid metabolism influences macrophage phenotype and function. These insights offer potential therapeutic strategies for immune-mediated diseases and inflammation-related disorders, including inflammaging.