O014 Critical role of Th17 pro-inflammatory cytokines to delay skin wound healing

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2012-09, Vol.59 (3), p.503-503
• Main Authors: Paris, I., Charreau, S., Guignouard, E., Garnier, M., Favot-Laforge, L., Huguier, V., Bernard, F.-X., Morel, F., Lecron, J.-C.
• Format: Article
• Language: English
• Subjects: Animal models; Chemokines; Differentiation; Helper cells; Inflammation; Inoculation; Interleukin 17; Interleukin 22; Interleukin 6; Keratinocytes; Kinetics; Lymphocytes T; oncostatin M; Pathogens; Pseudomonas aeruginosa; Skin diseases; Staphylococcus aureus; Supplementation; Tumor necrosis factor; Wound healing
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2012.06.043

The presence of pathogens in skin wound is known to delay wound healing. We previously shown that the proinflammatory cytokines Th17 (IL-22 and IL-17A and F) in combination with TNF, IL-1β and oncostatin M (OSM, IL-6 family) synergistically induce in vitro and in vivo the production of antibacterial peptides and chemokines by human and mouse keratinocytes (Guilloteau et al., J Immunol. 2010), promote proliferation and inhibit their differentiation. In order to investigate the presence and the role of these cytokines during wound healing, we developed a C57BL/6 mouse model of cutaneous wound healing, with or without inoculation of wounds by the bacteria S. aureus and P. aeruginosa, able to infect skin. Wound excision on mice induces the early expression of IL-1β, TNF and OSM, but the expression of IL-22 and IL-17A/ F is not detected so far. Bacteria wound inoculation not only increases the expression of IL-1β, TNF and of OSM, but induce a strong expression of IL-22 and IL-17A and F. A same expression pattern is observed in infected human skin wounds. Injection of these five cytokines in the wound edges induce a delayed wound healing similar to that induced by the bacterial mixture. The same experiments in septic conditions but in RAG2-KO mice (deficient in mature lymphocytes) show an accelerated wound healing kinetic, comparable to that of uninfected wild type mice. RAG2-KO skin lesions expressed IL-1β and OSM as wild type mice do, whereas expression of IL-17 and IL-22 is weak or no detectable. It shows that the expression of these cytokines is dependent on the presence of T cells. Finally, supplementation of infected wound edges of RAG2-KO mice by a IL-22, IL-17A and IL-17F mixture delays wound healing at the same level as that of infected wild type mice. These results demonstrate the synergistic and specific effects of IL-22 and IL-17 in the wound healing delay process, regardless of the presence of bacteria intra se.