12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.
Bottom Line: 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.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.
Affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.Show MeSH
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Mentions: The involvement of TNF and MMP9 in cell migration was also investigated in mouse primary keratinocytes isolated from BLT2 WT and BLT2 KO mice. 12-HHT significantly up-regulated the transcription of TNF only in BLT2 WT keratinocytes but not in BLT2 KO keratinocytes (Fig. 8 A). Both MMP9 mRNA (Fig. 8 B) and MMP9 protein levels (Fig. 8 C) were significantly higher in BLT2 WT keratinocytes. The mouse TNF-neutralizing antibody D2H4 only reduced the migration of BLT2 WT keratinocytes (Fig. 8 D). Collectively, these results clearly indicate that the 12-HHT/BLT2 axis accelerates keratinocyte migration by stimulating NF-κB signaling, which then induces the expression of TNF and MMP9 to promote wound healing.
Affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.