Tetsuya Hyodo1,2,3, Yoshiya Ito1,2, Kanako Hosono1,2, Satoshi Uematsu4, Shizuo Akira5, Masataka Majima6, Akira Takeda3, Hideki Amano7,2. 1. Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. 2. Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan. 3. Department of Plastic and Aesthetic Surgery, Kitasato University School of Medicine, Sagamihara, Japan. 4. Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka, Japan. 5. Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan. 6. Department of Medical Therapeutics, Kanagawa Institute of Technology, Atsugi, Japan. 7. Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan; hideki@med.kitasto-u.ac.jp.
Abstract
BACKGROUND/AIM: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E2 (PGE2) synthesis. PGE2 in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. MATERIALS AND METHODS: The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1-/-) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues. RESULTS: Angiogenesis was suppressed in mPGES-1-/- mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3+ Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1-/- mice than in WT mice. Neutralizing Tregs with antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice, but not in mPGES-1-/- mice. The topical application of PGE2 into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1-/- mice. CONCLUSION: Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE2 mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.
BACKGROUND/AIM: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E2 (PGE2) synthesis. PGE2 in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. MATERIALS AND METHODS: The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1-/-) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues. RESULTS: Angiogenesis was suppressed in mPGES-1-/- mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3+ Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1-/- mice than in WT mice. Neutralizing Tregs with antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice, but not in mPGES-1-/- mice. The topical application of PGE2 into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1-/- mice. CONCLUSION: Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE2 mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.
Authors: M Majima; M Isono; Y Ikeda; I Hayashi; K Hatanaka; Y Harada; O Katsumata; S Yamashina; M Katori; S Yamamoto Journal: Jpn J Pharmacol Date: 1997-10
Authors: Audrey Nosbaum; Nicolas Prevel; Hong-An Truong; Pooja Mehta; Monika Ettinger; Tiffany C Scharschmidt; Niwa H Ali; Mariela L Pauli; Abul K Abbas; Michael D Rosenblum Journal: J Immunol Date: 2016-01-29 Impact factor: 5.422