title: 12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.
abstract: Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein-coupled receptor (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive. As mouse BLT2 is highly expressed in epidermal keratinocytes, we investigated the role of the 12-HHT/BLT2 axis in skin wound healing processes. 12-HHT accumulated in the wound fluid in mice, and BLT2-deficient mice exhibited impaired re-epithelialization and delayed wound closure after skin punching. Aspirin administration reduced 12-HHT production and resulted in delayed wound closure in wild-type mice, which was abrogated in BLT2-deficient mice. In vitro scratch assay using primary keratinocytes and a keratinocyte cell line also showed that the 12-HHT/BLT2 axis accelerated wound closure through the production of tumor necrosis factor α (TNF) and matrix metalloproteinases (MMPs). A synthetic BLT2 agonist accelerated wound closure in cultured cells as well as in C57BL/6J and diabetic mice. These results identify a novel mechanism underlying the action of the 12-HHT/BLT2 axis in epidermal keratinocytes and accordingly suggest the use of BLT2 agonists as therapeutic agents to accelerate wound healing, particularly for intractable wounds, such as diabetic ulcers.
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan ksaeki@juntendo.ac.jp yokomizo-tky@umin.ac.jp.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Matsunobu
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Pharmaceutical Biochemistry, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Department of Metabolism and Atherosclerosis, Osaka University, Osaka 565-0871, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Yokoyama
authors.affiliation: Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakamizo
authors.affiliation: Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Department of Dermatology and Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo 162-0052, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan ksaeki@juntendo.ac.jp yokomizo-tky@umin.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism* / Q000503:physiopathology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018102:Receptors, Leukotriene B4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D005231:Fatty Acids, Unsaturated; D053583:Interleukin-1beta; C412867:Ltb4r2 protein, mouse; D018102:Receptors, Leukotriene B4; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D020780:Matrix Metalloproteinase 9