Abstract
The immunomodulatory activity of flavonoids is increasingly appreciated. Macrophage phospholipids (PLs) play crucial roles in cell-mediated inflammatory responses. However, little is known on how these PLs are affected upon flavonoid treatment. In this work, we have used mass-spectrometry-based lipidomics to characterize the changes in the phospholipidome of proinflammatory human-macrophage-like cells (THP-1-derived and LPS+IFN-γ-stimulated) incubated with non-cytotoxic concentrations of three flavonoids: quercetin, naringin and naringenin. One hundred forty-seven PL species belonging to various classes were identified, and their relative abundances were determined. Each flavonoid displayed its own unique signature of induced effects. Quercetin produced the strongest impact, acting both on constitutive PLs (phosphatidylcholines, phosphatidylethanolamines and sphingomyelins) and on minor signaling lipids, such as phosphatidylinositol (PI) and phosphatidylserine (PS) species. Conversely, naringin hardly affected structural PLs, producing changes in signaling molecules that were opposite to those seen in quercetin-treated macrophages. In turn, albeit sharing some effects with quercetin, naringenin did not change PI and PS levels and interfered with a set of phosphatidylcholines distinct from those modulated by quercetin. These results demonstrate that flavonoids bioactivity involves profound and specific remodeling of macrophage phospholipidome, paving the way to future studies on the role of cellular phospholipids in flavonoid-mediated immunomodulatory effects.
Highlights
Inflammation is a complex physiological response to potentially harmful stimuli, with a fundamental role in protecting and restoring homeostasis [1]
We found that quercetin, naringenin and, to a lesser extent, naringin significantly modulated the polar metabolome of prepolarized M1 macrophages, mainly towards downregulation of glycolysis and reprogramming of the tricarboxylic acid (TCA) cycle
In the present study, we investigate the impact of quercetin, naringin and naringenin on the phospholipidome of proinflammatory macrophages
Summary
Inflammation is a complex physiological response to potentially harmful stimuli, with a fundamental role in protecting and restoring homeostasis [1]. Non-resolving inflammatory responses can have deleterious consequences. Low-grade chronic inflammation has been implicated in the pathogenesis of several diseases (e.g., atherosclerosis, type 2 diabetes mellitus, rheumatoid arthritis) [2], as well as in the rejection of transplant organs and medical implants [3]. Macrophages are phagocytic innate immune cells with a crucial role in inflammation [1,4]. Molecules 2020, 25, 3460; doi:10.3390/molecules25153460 www.mdpi.com/journal/molecules (M1-like) to anti-inflammatory (M2-like), whose balance is crucial for an adequate onset and a timely resolution of inflammation [5]. Modulation of macrophage polarization has emerged as an attractive strategy in various medical contexts [6,7]
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