Lysophospholipid Receptors, As Novel Danger Associated Molecular Pattern Receptors And Homeostasis Associated Molecular Pattern Receptors Modulate Inflammation – Novel Paradigm And Therapeutic Potential

Abstract

To determine whether lysophospholipids (LPLs) serve as danger‐associated molecular pattern molecules (DAMPs) in initiating inflammations, we analyzed the tissue expressions of all 26 LPL receptors in 23 human tissues and 21 mouse tissues. We also examined the expression changes of the 26 LPL receptors in five prototypic chronic sterile inflammations including rheumatoid arthritis (RA), metabolic inflammatory diseases such as coronary artery disease (CAD), metabolic syndrome, type 2 diabetes and type 1 diabetes. We made the following important findings: 1) Three LPLs including lysophosphatidylinositol (LPI), lysophosphatidylserine (LysoPS) and lysophosphatidylethanolamine (LPE) bind to two specific G protein‐coupled LPLs receptors (LPL‐GPCRs) while other four LPLs bind to more than five LPL‐GPCRs, respectively; 2) Lysophosphatidic acid (LPA), lysophingolipid sphingosine 1‐phosphate (S1P) and lysoyphosphatidylcholine (LPC) have ubiquitous physiological signaling functions among tissues whereas other LPLs, especially LPI, may have tissue‐specific functions; 3) The expressions of certain LPL‐GPCRs are significantly upregulated in human and mouse RA, CAD, and other metabolic inflammatory diseases; 4) Mechanistically, pro‐inflammatory cytokine signaling regulates the expressions of LPL receptors; 5) Toll‐like receptor (TLR), presumably bound by other DAMPs, regulates the expressions of LPL receptors; and 6) In cross‐talking, LPL receptor signaling regulates the expressions of TLRs; 7) We propose for the first time that, in parallel to the well‐accepted danger associated molecular pattern receptor model, novel homeostasis‐associated molecular pattern molecules (HAMPs) receptors (HAMPRs) are the receptors for binding to signals that are generated from endogenous metabolic processes and can initiate anti‐inflammatory/homeostatic signaling and promote inflammation resolution. From this point of view, we propose a new paradigm of that LPLs are either pro‐inflammatory DAMPs or anti‐inflammatory HAMPs for regulating the onset of inflammation, inhibition of inflammation, and resolution of inflammation. This new paradigm and new concept of HAMP receptors would significantly improve our understanding on the roles of LPLs and other endogenous metabolites in regulating the pathogenesis of inflammations and eventually lead to the future development of novel therapeutics for rheumatoid diseases, metabolic inflammatory diseases, cardiovascular diseases, and inflammatory cancers.Support or Funding InformationNIH RO1 HL 108910‐01