title: Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFRα(+) mesenchymal cells from bone marrow.
abstract: High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFRα(+) mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFRα(+) mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFRα(+) mesenchymal cells showed massive inflammation of the grafts compared to mice that had normal levels of these cells even after HMGB1 administration, suggesting that BM-PDGFRα(+) mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM-PDGFRα(+) mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on these cells. Finally, we showed the therapeutic activity of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in an allergic contact dermatitis model. The results illustrated the contribution of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases.
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Aikawa
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Fujita
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.affiliation: Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D024243:HMGB1 Protein / Q000008:administration & dosage*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D000893:Anti-Inflammatory Agents; C514936:CXCR4 protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D019718:Receptors, CXCR4; D020796:Receptor, Platelet-Derived Growth Factor alpha