title: Inducible costimulator (ICOS) and ICOS ligand signaling has pivotal roles in skin wound healing via cytokine production.
abstract: Skin wound healing is mediated by inflammatory cell infiltration of the wound site. Inducible costimulator (ICOS), expressed on activated T cells, and its ligand, ICOS ligand (ICOSL), expressed on antigen-presenting cells, have been considered a single receptor-ligand pair. Although the ICOS-ICOSL pathway participates in adaptive immunity, its roles in skin wound healing, which is mediated by innate immune responses, remain unknown. To clarify these roles, repair of excisional wounds was examined in ICOS(-/-) mice, ICOSL(-/-) mice, and ICOS(-/-)ICOSL(-/-) mice. Each mutant strain showed similar, dramatic delays in wound healing, especially at early times. Knockout mice showed suppressed keratinocyte migration, angiogenesis, and granulation tissue formation, and diminished T-cell, macrophage, and neutrophil infiltration. The loss of ICOS and/or ICOSL resulted in marked suppression of cytokine expression in wounds, especially the Th2 cytokines interleukin (IL)-4, IL-6, and IL-10. T-cell transfer experiments and T-cell depletion therapy further clarified the important roles of ICOS expressed on T cells and its interaction with ICOSL. Application of IL-6, but not IL-4, to the wounds significantly increased the onset of early wound healing in mutant mice. Thus, our results indicate that ICOS-ICOSL costimulatory signaling has critical roles during wound healing, most likely by inducing IL-6 production.
authors.affiliation: Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Maeda
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis* / Q000494:pharmacology; D006097:Granulation Tissue / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D015603:Keratinocytes / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058628:Myofibroblasts / Q000502:physiology; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D012867:Skin / Q000098:blood supply / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014945:Wound Healing / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D015850:Interleukin-6; D015847:Interleukin-4