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.

Keywords: COVID-19; atherosclerosis; immunometabolism; inflammasome; inflammation; lung; oxPAPC; oxidized phospholipids.

Figure 1

oxPAPC boosts inflammatory responses in LPS-activated macrophages. Upon LPS encounter and/or during atherosclerosis development, oxPAPC induces a metabolic remodeling state in phagocytes, termed hypermetabolism, that is characterized by 1) boosting of mitochondrial activity via iNOS inhibition and ETC protection; 2) sustaining the TCA cycle with glutamine and upregulation of IDH; and 3) upregulating ACLY. These events result in the conversion of citrate to OAA, which in turn stabilizes HIF-1α and increases production of pro-IL-1β. OxPAPC is also transported into the cytosol via the endocytic module CD14-SYK-PLCγ, where it interacts with caspse-11/4 and induces oligomerization of this enzyme. oxPAPC may also interact with caspase-1, to form caspase-11/4/5-1 hetero-complexes, or to activate the NLRP3 inflammasome. These processes, termed hyperactivation, lead to IL-1β cleavage and release, but not to pyroptosis.

Figure 2

oxPAPC triggers and sustains inflammation in atherosclerosis and viral lung infections. During atherosclerosis (left) oxPAPC released from dying cells or contained in oxLDL induces the release of chemokines and ATP from endothelial cells (red). Phagocytes (blue) become hyperinflammatory, modify their metabolism, and produce pro-inflammatory cytokines such as IL-1β and IL-6. IL-1β can also be induced by extracellular stressors such as ATP. In this manner, the endothelial cell-phagocyte circuit sustains inflammation. During viral infections (right), oxPAPC released from infected-dead cells or from surfactant oxidation interacts with endothelial cells (red) that produce chemokines and TF. Low doses of oxPAPC (early steps of infection) elicit barrier function, while high doses of oxPAPC (late steps of infections) disrupt the endothelial barrier. Phagocytes (blue) activate inflammasome-dependent responses, secrete cytokines and TF and lead to inflammation and coagulation.