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12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.

Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T - J. Exp. Med. (2014)

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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.

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BLT2 is expressed in epidermal keratinocytes, and the ligand 12-HHT is produced in coagulated blood and wound exudate, in a COX/TxA2S-dependent manner. (A and B) Relative BLT2 mRNA levels were measured by Q-PCR in mouse primary epidermal keratinocytes and dermal fibroblasts (A; n = 3 mice per group) and NHEKs and normal human dermal fibroblasts (NHDFs; B; n = 3 experimental replicates, P = 0.16, unpaired Student’s t test). (C) Immunohistochemical staining with anti–mouse BLT2 antibody and control rabbit IgG is shown in normal (uninjured) mouse skin. Arrows, BLT2 signals; arrowheads, nonspecific staining. Bars, 100 µm. (D) Immunohistochemical staining with (right) or without (left) anti–human BLT2 antibody is shown in normal (uninjured) human skin. Bars, 100 µm. (E) Biosynthesis and proposed mechanism of action of 12-HHT. (F and G) 12-HHT was quantified in mouse serum (F) and mouse wound fluid (G) by LC-MS/MS (n = 3–5 mice per group). Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and B, unpaired Student’s t test; F, one-way ANOVA with Bonferroni post hoc tests; G, two-way ANOVA with Bonferroni post hoc tests). All the results are representative of at least two independent experiments.
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fig1: BLT2 is expressed in epidermal keratinocytes, and the ligand 12-HHT is produced in coagulated blood and wound exudate, in a COX/TxA2S-dependent manner. (A and B) Relative BLT2 mRNA levels were measured by Q-PCR in mouse primary epidermal keratinocytes and dermal fibroblasts (A; n = 3 mice per group) and NHEKs and normal human dermal fibroblasts (NHDFs; B; n = 3 experimental replicates, P = 0.16, unpaired Student’s t test). (C) Immunohistochemical staining with anti–mouse BLT2 antibody and control rabbit IgG is shown in normal (uninjured) mouse skin. Arrows, BLT2 signals; arrowheads, nonspecific staining. Bars, 100 µm. (D) Immunohistochemical staining with (right) or without (left) anti–human BLT2 antibody is shown in normal (uninjured) human skin. Bars, 100 µm. (E) Biosynthesis and proposed mechanism of action of 12-HHT. (F and G) 12-HHT was quantified in mouse serum (F) and mouse wound fluid (G) by LC-MS/MS (n = 3–5 mice per group). Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and B, unpaired Student’s t test; F, one-way ANOVA with Bonferroni post hoc tests; G, two-way ANOVA with Bonferroni post hoc tests). All the results are representative of at least two independent experiments.

Mentions: To determine the cells that express BLT2 in skin, we performed a quantitative reverse transcription polymerase chain reaction (Q-PCR) analysis along with immunohistochemical staining to investigate BLT2 expression in skin cells and intact skin, respectively. BLT2 mRNA was prominently detected in both mouse and human epidermal keratinocytes, but not in dermal fibroblasts (Fig. 1, A and B). Immunohistochemical staining revealed that BLT2 was mainly expressed in the epidermal layer of normal (uninjured) mouse and human skin (Fig. 1 C and D).


12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.

Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T - J. Exp. Med. (2014)

BLT2 is expressed in epidermal keratinocytes, and the ligand 12-HHT is produced in coagulated blood and wound exudate, in a COX/TxA2S-dependent manner. (A and B) Relative BLT2 mRNA levels were measured by Q-PCR in mouse primary epidermal keratinocytes and dermal fibroblasts (A; n = 3 mice per group) and NHEKs and normal human dermal fibroblasts (NHDFs; B; n = 3 experimental replicates, P = 0.16, unpaired Student’s t test). (C) Immunohistochemical staining with anti–mouse BLT2 antibody and control rabbit IgG is shown in normal (uninjured) mouse skin. Arrows, BLT2 signals; arrowheads, nonspecific staining. Bars, 100 µm. (D) Immunohistochemical staining with (right) or without (left) anti–human BLT2 antibody is shown in normal (uninjured) human skin. Bars, 100 µm. (E) Biosynthesis and proposed mechanism of action of 12-HHT. (F and G) 12-HHT was quantified in mouse serum (F) and mouse wound fluid (G) by LC-MS/MS (n = 3–5 mice per group). Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and B, unpaired Student’s t test; F, one-way ANOVA with Bonferroni post hoc tests; G, two-way ANOVA with Bonferroni post hoc tests). All the results are representative of at least two independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig1: BLT2 is expressed in epidermal keratinocytes, and the ligand 12-HHT is produced in coagulated blood and wound exudate, in a COX/TxA2S-dependent manner. (A and B) Relative BLT2 mRNA levels were measured by Q-PCR in mouse primary epidermal keratinocytes and dermal fibroblasts (A; n = 3 mice per group) and NHEKs and normal human dermal fibroblasts (NHDFs; B; n = 3 experimental replicates, P = 0.16, unpaired Student’s t test). (C) Immunohistochemical staining with anti–mouse BLT2 antibody and control rabbit IgG is shown in normal (uninjured) mouse skin. Arrows, BLT2 signals; arrowheads, nonspecific staining. Bars, 100 µm. (D) Immunohistochemical staining with (right) or without (left) anti–human BLT2 antibody is shown in normal (uninjured) human skin. Bars, 100 µm. (E) Biosynthesis and proposed mechanism of action of 12-HHT. (F and G) 12-HHT was quantified in mouse serum (F) and mouse wound fluid (G) by LC-MS/MS (n = 3–5 mice per group). Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and B, unpaired Student’s t test; F, one-way ANOVA with Bonferroni post hoc tests; G, two-way ANOVA with Bonferroni post hoc tests). All the results are representative of at least two independent experiments.
Mentions: To determine the cells that express BLT2 in skin, we performed a quantitative reverse transcription polymerase chain reaction (Q-PCR) analysis along with immunohistochemical staining to investigate BLT2 expression in skin cells and intact skin, respectively. BLT2 mRNA was prominently detected in both mouse and human epidermal keratinocytes, but not in dermal fibroblasts (Fig. 1, A and B). Immunohistochemical staining revealed that BLT2 was mainly expressed in the epidermal layer of normal (uninjured) mouse and human skin (Fig. 1 C and D).

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.

View Article: PubMed Central - HTML - PubMed

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
Related in: MedlinePlus