title: Interleukin-22 Promotes Wound Repair in Diabetes by Improving Keratinocyte Pro-Healing Functions.
abstract: Impaired re-epithelialization, imbalanced expression of cytokines and growth factors, and vascular disease contribute to healing impairment in diabetes. IL-22, a pro-inflammatory cytokine mediating a cross-talk between immune system and epithelial cells, has been shown to have a role in repair processes. In this study we aimed to investigate IL-22 regenerative potential in the poor healing context of diabetic wounds. By using streptozotocin-induced diabetic mice, we demonstrated that IL-22 wound treatment significantly accelerated the healing process, by promoting re-epithelialization, granulation tissue formation, and vascularization. Improved re-epithelialization was associated with increased keratinocyte proliferation and signal transducer and activator of transcription 3 (STAT3) activation. We showed that endogenous IL-22 content was reduced at both mRNA and protein level during the inflammatory phase of diabetic wounds, with fewer IL-22-positive cells infiltrating the granulation tissue. We demonstrated that IL-22 treatment promoted proliferation and injury repair of hyperglycemic keratinocytes and induced activation of STAT3 and extracellular signal-regulated kinase transduction pathways in keratinocytes grown in hyperglycemic condition or isolated from diabetic patients. Finally, we demonstrated that IL-22 treatment was able to inhibit diabetic keratinocyte differentiation while promoting vascular endothelial growth factor release. Our data indicate a pro-healing role of IL-22 in diabetic wounds, suggesting a therapeutic potential for this cytokine in diabetic ulcer management.
authors.affiliation: Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Avitabile
authors.affiliation: Laboratory of Biochemistry, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Odorisio
authors.affiliation: Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Madonna
authors.affiliation: ZAUM - Center of Allergy and Environment, Technische Universität and Helmholtz Center, Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Eyerich
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Guerra
authors.affiliation: Department of Dermatology and Allergy, Technische Universität, Munich, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Eyerich
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy. Electronic address: f.cianfarani@idi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavani
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy. Electronic address: f.cianfarani@idi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cianfarani
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D012883:Skin Ulcer / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000097043:Interleukin-22