Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury

Abstract

Significance: We proposed lysophospholipids (LPLs) and LPL-G-protein-coupled receptors (GPCRs) as conditional danger-associated molecular patterns (DAMPs) and conditional DAMP receptors as a paradigm shift to the widely accepted classical DAMP and DAMP receptor model. Recent Advances: The aberrant levels of LPLs and GPCRs activate pro-inflammatory signal transduction pathways, trigger innate immune response, and lead to tissue oxidative and inflammatory injury. Critical Issues: Classical DAMP model specifies only the endogenous metabolites that are released from damaged/dying cells as DAMPs, but fails to identify elevated endogenous metabolites secreted from viable/live cells during pathologies as DAMPs. The current classification of DAMPs also fails to clarify the following concerns: (i) Are molecules, which bind to pattern recognition receptors (PRRs), the only DAMPs contributing to inflammation and tissue injury? (ii) Are all DAMPs acting only via classical PRRs during cellular stress? To answer these questions, we reviewed the molecular characteristics and signaling mechanisms of LPLs, a group of endogenous metabolites and their specific receptors and analyzed the significant progress achieved in characterizing oxidative stress mechanisms of LPL mediated tissue injury. Future Directions: Further LPLs and LPL-GPCRs may serve as potential therapeutic targets for the treatment of pathologies induced by sterile inflammation. Antioxid. Redox Signal. 28, 973-986.

Keywords: G-protein-coupled receptors; conditional danger-associated molecular patterns; inflammation; lysophospholipids; mitochondrial reactive oxygen species; oxidative stress.

FIG. 1.

Biosynthetic pathways of lysophospholipids. Phospholipases A1 and A2 are common enzymes in converting PC to LPC, PA to LPA, PI to LPI, whereas both LPI and LPC converge to LPA mediated by phospholipase D and autotaxin, respectively. LPA, lysoPA; LPC, lysoPC; LPI, lysoPI; PA, phosphatidic acid; PC, phosphatidylcholine; PI, phosphatidylinositol. CDS, CDP-DAG synthase; CTP, cytidine 5′-triphosphate; CPD-DAG, cytidine diphosphate diacylglycerol; DAG, diacylglycerol; DGK, diacylglycerol kinase; LCAT, lecithin-cholesterol acyltransferase; LPPs, lipid phosphate phosphohydrolases; LysoPLD, lysophospholipase D; PA, phosphatidic acid; PC, phosphatidyl choline; PDCT, phosphatidylcholine diacylglycerol cholinephosphotransferase; PI, phosphatidylinositol; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D; SMS, sphingomyelin synthase; SphK, sphingosine kinase; SPP, sphingophospholipid phosphatase.

FIG. 2.

The specificities of LPLs signaling via GPCRs. Four types of G-protein coupled receptors G12/13, Gq, Gi, and Gs and their downstream components mediate LPL signaling. LPLs, lysophospholipids; GPCRs, G-protein-coupled receptors.

FIG. 3.

LPLs via LPL-GPCR signaling activate innate immunity and inflammation by sharing the downstream targets of classical PRRs. LPLs may act as conditional DAMPs, which collaborate with classical DAMP receptors (or pathogen-associated molecular patterns receptors, PRRs) and initiate signaling via NF-κB/AP-1/CREB-mediated pro-inflammatory cytokine transcription, ROS/mitochondrial ROS signaling, and posttranslational caspase-1/NLRP3 inflammasome pathways. DAMPs, danger-associated molecular patterns. AP-1, activator protein-1; CREB, cAMP (cyclic adenosine monophosphate) response element binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PRRs, pattern recognition receptors; ROS, reactive oxygen species; mtROS, mitochondrial ROS.To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

A schematic illustration of aberrant LPLs accelerating vascular oxidative stress and inflammation as DAMPs via GPCRs. The levels of ROS (cytosolic ROS) and determine, from low to high levels, endothelial activation; VSMC phenotypic switch; matrix metalloproteinase induction; and cell death, respectively; and lysoPC-induced, increased proton leak-mediated, ATP synthesis uncoupled mtROS regulate physiological endothelial activation for recruiting patrolling cells and pathological endothelial cell activation for recruiting inflammatory cells into aorta and tissues. ATP, adenosine triphosphate; VSMC, vascular smooth muscle cell. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars