Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury.
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 onlyviaclassical 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.
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Ying
Y
Shao
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Gayani
G
Nanayakkara
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Jiali
J
Cheng
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Ramon
R
Cueto
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
William Y
WY
Yang
Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania.
Joon-Young
JY
Park
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Hong
H
Wang
Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Xiaofeng
X
Yang
G-protein-coupled receptors; conditional danger-associated molecular patterns; inflammation; lysophospholipids; mitochondrial reactive oxygen species; oxidative stress