ICOSL Stimulation by ICOS-Fc Accelerates Cutaneous Wound Healing In Vivo

Background: ICOS and its ligand ICOSL are immune receptors whose interaction triggers bidirectional signals that modulate the immune response and tissue repair. Aim: The aim of this study was to assess the in vivo effects of ICOSL triggering by ICOS‐Fc, a recombinant soluble form of ICOS, on skin wound healing. Methods: The effect of human ICOS‐Fc on wound healing was assessed, in vitro, and, in vivo, by skin wound healing assay using ICOS−/− and ICOSL−/− knockout (KO) mice and NOD‐SCID‐IL2R null (NSG) mice. Results: We show that, in wild type mice, treatment with ICOS‐Fc improves wound healing, promotes angiogenesis, preceded by upregulation of IL‐6 and VEGF expression; increases the number of fibroblasts and T cells, whereas it reduces that of neutrophils; and increases the number of M2 vs. M1 macrophages. Fittingly, ICOS‐ Fc enhanced M2 macrophage migration, while it hampered that of M1 macrophages. ICOS−/− and ICOSL−/− KO, and NSG mice showed delayed wound healing, and treatment with ICOS‐Fc improved wound closure in ICOS−/− and NSG mice. Conclusion: These data show that the ICOS/ICOSL network cooperates in tissue repair, and that triggering of ICOSL by ICOS‐Fc improves cutaneous wound healing by increasing angiogenesis and recruitment of reparative macrophages.