Dooming Phagocyte Responses: Inflammatory Effects of Endogenous Oxidized Phospholipids

Abstract

Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.

Innate immune detection of lipid oxidation as a threat assessment strategy

“…This unusual macrophage phenotype was observed in atherosclerotic plaques of Ldlr −/− mice. Additional details about the metabolic activities of oxPLs in phagocytes are described in a recent review 43 .…”

“…In contrast to LPS, oxPAPCs did not induce TLR4 dimerization and endocytosis, myddosome formation or the expression of proinflammatory cytokines in macrophages 21 . However, in the context of animals, in which exposures to microbial products are difficult to control, oxPAPCs exhibit proinflammatory responses via TLR4 (refs 14 , 43 ). Upon lung injury, oxPAPCs promoted IL-6 secretion from alveolar macrophages, and played a critical role in lung disease pathogenesis via a TLR4–TICAM pathway.…”

“…Neutralization of oxPAPCs by the antibody E06 attenuated IL-6 production in the bronchoalveolar fluid. Furthermore, Shirey et al described strong inhibition of oxPAPC-induced IL-6 production after treatment with the TLR4 antagonist eritoran 43 . Thus, in airways, oxPAPCs are potent stimulators of inflammation.…”

Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review

“…Nowadays, it is recognized that lipid metabolism, in particular phospholipid and sphingolipid metabolism, is altered in psychiatric disorders, and may contribute to the etiology of these diseases. For instance, in MDD increased lipid peroxidation, derived from increased oxidative stress, as well as an inflammatory state, can induce changes in the lipid profile of the brain and in lipid metabolism, but also in lipids involved in signaling [22][23][24]. MDD treatment is also accompanied by changes in lipid metabolism [14,15].…”

The Pathomechanism, Antioxidant Biomarkers, and Treatment of Oxidative Stress-Related Eye Diseases

“…Peroxidized cell membrane phospholipids can be recognized by scavenger receptors or toll-like receptors and thus induce programmed cell death [14]. Oxidized phospholipids can also activate proinflammatory molecules and thus cause inflammation [15]. The protein modifications induced by ROS can affect the function of structural proteins, the activity of enzymatic proteins, and signal transduction pathways (e.g., redox-sensitive pathways) [16].…”