P073 Inhibition of keratinocyte differentiation by the synergistic effect of pro-inflammatory cytokines

Integrity of the epidermal barrier is based on a tight regulation of the communication between keratinocytes and immune cells, particularly provided by the balanced cytokine production. An imbalance network leads to appearance of skin inflammatory diseases such as psoriasis. Our work has identified a part of this cytokine network in psoriatic lesions. Modeling of skin inflammation showed that combination of IL-1a, IL-17A, IL-22, OSM and TNF a synergistically increases expression of chemokines and antimicrobial peptides, leading to massive neutrophil skin infiltration, recapitulating some features of psoriasis. The aim of our study was to investigate the impact of these cytokines on keratinocyte differentiation. If IL-1a, IL-17A, IL-22, OSM or TNFa were able to decrease expressions of cytokeratin 10 (K10), loricrin (LOR), filaggrin (FLG) and cadherin 1 (CDH1), IL-22, OSM and TNFa were the most powerful. Combination of these 5 cytokines (M5) generated a synergistic effect on inhibition of expression for these markers of differentiation. These results were confirmed on reconstructed epidermis (RHE). IL-22 and OSM significantly decreased expressions of K10, FLG and CDH1 and induced epidermal hyperplasia. Injection of the M5 in vivo in mice caused a thickening of the skin associated with decreased expression of K10, FLG and CDH1. Similarly we have demonstrated a significant decrease in the expression of these markers in skin lesions of psoriasis patients, showing an expression profile similar to those obtained in vitro and in vivo. Our results showed that synergistic effect of M5 was responsible for the production of antimicrobial peptides, chemokines and the inhibition of keratinocyte differentiation. If IL-1a, IL-17A and TNFa were important for the production of antimicrobial peptides and chemokines, IL-22, OSM and TNFa seemed essential to the differentiation inhibition. Establishment of these models should clarify the role of these cytokines in the establishment of the inflammatory response.