Key result
Native LDL drives THP1 monocyte differentiation into M1 macrophages more efficiently than PMA in vitro.
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Obesity-derived biomolecules such as LDL, ox-LDL, and PGE2 can act as non-canonical stimuli for macrophage differentiation, providing a mechanistic link between obesity, low-grade inflammation, and cardiovascular disease.
BACKGROUND: It is well known that the microenvironment in which an immune response develops, generally pro-inflammatory or immunosuppressive, along with other overproduced biomolecules recognized by pattern recognition receptors, may promote the stimulation and differentiation of monocytes into macrophages with effector functions. Low-density lipoprotein (LDL) plays a fundamental role in cholesterol transport. By contrast, its oxidized form (ox-LDL), which is overexpressed in conditions of obesity and chronic low-grade inflammation, has been associated with cardiovascular diseases. Depending on the microenvironmental context, prostaglandin E2 (PGE2) participates in various scenarios such as inflammation, anti-inflammation, and homeostasis. Therefore, obesity-derived biomolecules such as LDL, ox-LDL, and PGE2 could induce the differentiation of immune cells into effector populations with either pro-inflammatory or immunosuppressive profiles. METHODS: In the present work, we studied the effects of LDL, ox-LDL, and PGE2 on the differentiation of the human THP1 monocytic cell line into macrophages under two different protocols, analyzing several activation markers associated with either pro-inflammatory M1 or anti-inflammatory M2 profiles by flow cytometry and quantitative PCR (qPCR). RESULTS: Our data suggest that native LDL induces the differentiation of human THP1 monocytes into M1 macrophages even more efficiently than classic phorbol 12-myristate 13-acetate (PMA) stimulation, whereas ox-LDL and PGE2 induce the expression of activation markers similarly to interferon gamma or interleukin 4 during PMA preactivation of macrophages. CONCLUSIONS: The results of this study add evidence to the role of obesity-derived biomolecules as non-canonical differentiation stimuli in macrophages, which could be relevant in contexts where these biomolecules are chronically overproduced, such as obesity, low-grade inflammation, type 2 diabetes, and cancer.
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Terrazas et al. (2025) studied this question. Obesity-derived biomolecules (LDL, ox-LDL, and PGE2) vs. Phorbol 12-myristate 13-acetate (PMA), interferon gamma, or interleukin 4 was evaluated on Differentiation into M1 or M2 macrophages and expression of activation markers. Native LDL induced the differentiation of human THP1 monocytes into M1 macrophages more efficiently than classic PMA stimulation in vitro.
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