Platelet Activating Factor

Glycerol-based ether lipids including ether phospholipids form a specialized branch of lipids that in mammals require peroxisomes for their biosynthesis. They are major components of biological membranes and one particular subgroup, the plasmalogens, is widely regarded as a cellular antioxidant. Their vast potential to influence signal transduction pathways is less well known. Here, we summarize the literature showing associations with essential signaling cascades for a wide variety of ether lipids, including platelet-activating factor, alkylglycerols, ether-linked lysophosphatidic acid and plasmalogen-derived polyunsaturated fatty acids. The available experimental evidence demonstrates links to several common players like protein kinase C, peroxisome proliferator-activated receptors or mitogen-activated protein kinases. Furthermore, ether lipid levels have repeatedly been connected to some of the most abundant neurological diseases, particularly Alzheimer's disease and more recently also neurodevelopmental disorders like autism. Thus, we critically discuss the potential role of these compounds in the etiology and pathophysiology of these diseases with an emphasis on signaling processes. Finally, we review the emerging interest in plasmalogens as treatment target in neurological diseases, assessing available data and highlighting future perspectives. Although many aspects of ether lipid involvement in cellular signaling identified in vitro still have to be confirmed in vivo, the compiled data show many intriguing properties and contributions of these lipids to health and disease that will trigger further research.

G protein-coupled receptors (GPCRs) are important drug targets that mediate various signaling pathways by activating G proteins and engaging β-arrestin proteins. Despite its importance for the development of therapeutics with fewer side effects, the underlying mechanism that controls the balance between these signaling modes of GPCRs remains largely unclear. Here, we show that assembly into dimers and oligomers can largely influence the signaling mode of the platelet-activating factor receptor (PAFR). Single-particle analysis results show that PAFR can form oligomers at low densities through two possible dimer interfaces. Stabilization of PAFR oligomers through cross-linking increases G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. Reciprocally, β-arrestin prevents PAFR oligomerization. Our results highlight a mechanism involved in the control of receptor signaling, and thereby provide important insights into the relationship between GPCR oligomerization and downstream signaling.

BackgroundAlthough plasma leakage is the hallmark of severe dengue infections, the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF) is associated with an increase in vascular permeability in other diseases, we set out to investigate its role in acute dengue infection.Materials and methodsPAF levels were initially assessed in 25 patients with acute dengue infection to determine if they were increased in acute dengue. For investigation of the kinetics of PAF, serial PAF values were assessed in 36 patients. The effect of dengue serum on tight junction protein ZO-1 was determined by using human endothelial cell lines (HUVECs). The effect of dengue serum on and trans-endothelial resistance (TEER) was also measured on HUVECs.ResultsPAF levels were significantly higher in patients with acute dengue (n = 25; p = 0.001) when compared to healthy individuals (n = 12). In further investigation of the kinetics of PAF in serial blood samples of patients (n = 36), PAF levels rose just before the onset of the critical phase. PAF levels were significantly higher in patients with evidence of vascular leak throughout the course of the illness when compared to those with milder disease. Serum from patients with dengue significantly down-regulated expression of tight junction protein, ZO-1 (p = 0.004), HUVECs. This was significantly inhibited (p = 0.004) by use of a PAF receptor (PAFR) blocker. Serum from dengue patients also significantly reduced TEER and this reduction was also significantly (p = 0.02) inhibited by prior incubation with the PAFR blocker.ConclusionOur results suggest the PAF is likely to be playing a significant role in inducing vascular leak in acute dengue infection which offers a potential target for therapeutic intervention.

Myocardial ischemia-reperfusion (MI/R) injury remains a critical challenge in cardiovascular therapeutics, with metabolic-inflammatory signaling axis emerging as a critical mediator of pathological outcomes. Yet, the specific metabolic pathways interplay with inflammation to exacerbate MI/R injury remain poorly defined. Here we verify that NETosis of neutrophils is an initiative and causal factor in driving MI/R injury, specifically, platelet activating factor (PAF) secreted by cardiomyocytes during MI/R, drives neutrophil extracellular traps (NETs) formation and subsequent NETosis. Increased expression of PAF synthesis enzyme PLA2G6 explains excessive production of PAF. PAF-induced NETosis requires gasdermin D (GSDMD) mediated pore-forming to facilitate NETs extrusion. Both inhibiting NETs and PAF synthesis significantly alleviate MI/R injury. We further identify dapagliflozin as a potent NETosis inhibitor that protects mice from MI/R injury in a sodium-glucose co-transporter 2 (SGLT2)-independent manner, which targets neutrophil gelatinase-associated lipocalin-2 (LCN2). Notably, increased serum PAF concentration in acute myocardial infarction patients with percutaneous coronary intervention was positively correlated with NETosis and myocardial injury indexes. Of interest, patients receiving dapagliflozin exhibited attenuated myocardial injury in comparison to those without dapagliflozin. Collectively, our study demonstrates PAF serves as a danger signal in triggering NETosis in early MI/R injury, and manipulating PAF-NETosis signal by dapagliflozin or LCN2 inhibitor might be effective in combating MI/R injury.