title: Potentials of the circulating pruritogenic mediator lysophosphatidic acid in development of allergic skin inflammation in mice: role of blood cell-associated lysophospholipase D activity of autotaxin.
abstract: Itching and infiltration of immune cells are important hallmarks of atopic dermatitis (AD). Although various studies have focused on peripheral mediator-mediated mechanisms, systemic mediator-mediated mechanisms are also important in the pathogenesis and development of AD. Herein, we found that intradermal injection of lysophosphatidic acid (LPA), a bioactive phospholipid, induces scratching responses by Institute of Cancer Research mice through LPA1 receptor- and opioid μ receptor-mediating mechanisms, indicating its potential as a pruritogen. The circulating level of LPA in Naruto Research Institute Otsuka Atrichia mice, a systemic AD model, with severe scratching was found to be higher than that of control BALB/c mice, probably because of the increased lysophospholipase D activity of autotaxin (ATX) in the blood (mainly membrane associated) rather than in plasma (soluble). Heparan sulfate proteoglycan was shown to be involved in the association of ATX with blood cells. The sequestration of ATX protein on the blood cells by heparan sulfate proteoglycan may accelerate the transport of LPA to the local apical surface of vascular endothelium with LPA receptors, promoting the hyperpermeability of venules and the pathological uptake of immune cells, aggravating lesion progression and itching in Naruto Research Institute Otsuka Atrichia mice.
authors.affiliation: Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoshibumi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Technical Service Department, Clea Japan, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okudaira
authors.affiliation: Technical Service Department, Clea Japan, Tokyo, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kimoto
authors.affiliation: Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan. Electronic address: tokumura@tokushima-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Tokumura
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000201:enzymology*; D002462:Cell Membrane / Q000378:metabolism; D002853:Chromatography, Liquid; D006967:Hypersensitivity / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000097:blood* / Q000150:complications / Q000201:enzymology / Q000473:pathology; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D010727:Phosphoric Diester Hydrolases / Q000097:blood*; D011485:Protein Binding; D011537:Pruritus / Q000097:blood* / Q000150:complications / Q000201:enzymology / Q000473:pathology; D012867:Skin / Q000473:pathology*; D012995:Solubility; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D013110:Sphingosine; D000099189:Lysophospholipase D; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid