Macrophages: their role in immunity and their relationship with fatty acids in health and disease

Abstract

The intricate interplay between macrophage biology and lipid metabolism has emerged as a critical determinant of metabolic homeostasis, disease progression and pathogenesis. This comprehensive review explores the molecular mechanisms through which fatty acids activate macrophage function, emphasizing their selective engagement of pattern recognition receptors such as Toll-like receptors (TLRs), CD36, and GPR120. Notably, saturated fatty acids (SFAs) like lauric acid (C12:0) and palmitic acid (C16:0) activate TLR2 and TLR4 signaling pathways. Palmitic acid triggers mitochondrial dysfunction and lysosomal destabilization, leading to NLRP3 inflammasome activation and chronic low-grade inflammation. In contrast, ω-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid, help resolve inflammation through GPR120-mediated signaling and the production of specialized pro-resolving mediators (SPMs) like resolvins, protectins, and maresins. This review establishes a paradigm for understanding the complex relationship between dietary lipids, innate immunity, and metabolic health, with broad implications for immunometabolic interventions.

Keywords: fatty acids; immunometabolism; inflammation; macrophages; metabolic diseases.

Figure 1

Macrophage polarization in response to saturated and unsaturated fatty acids. Created in https://BioRender.com.

Figure 2

Overview of the main macrophage activation pathways induced by saturated (SFAs) and unsaturated fatty acids (UFAs, including MUFAs and PUFAs). Fatty acids regulate macrophage function by acting as both metabolic substrates and signaling molecules that shape inflammatory responses. SFAs are metabolized into triglycerides (TGs), contributing to endoplasmic reticulum (ER) stress and the activation of pro-inflammatory pathways involving CD36, ceramides, and reactive oxygen species (ROS), which trigger the NLRP3 inflammasome. This cascade promotes inflammation by disrupting membrane fluidity and enhancing TLR4-mediated NF-κB signaling, leading to the production of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β. In contrast, UFAs exert anti-inflammatory and pro-resolving effects. They activate GPR120, which engages multiple downstream pathways, including ERK, PI3K/AKT, and Ca²⁺ signaling, that collectively enhance glucose uptake and cell growth. UFAs also signal through CD36 and fatty acid-binding proteins (FABPs), which transport fatty acids to mitochondria for conversion to acetyl-CoA. Acetyl-CoA enters β-oxidation, facilitated by carnitine palmitoyl transferase 1 (CPT1), thereby enhancing mitochondrial respiration and reducing ROS levels. This metabolic shift supports the activation of PPAR-γ and the production of IL-10, reinforcing an M2 phenotype through feedback to CD36. Together, these pathways highlight the dual immunometabolic roles of fatty acids in macrophage polarization and suggest potential targets for therapeutic intervention in metabolic inflammatory diseases. Created in https://BioRender.com.