IL-12 protects from psoriasiform skin inflammation

• Published in: Nature communications Vol. 7; no. 1; pp. 13466 - 14
• Main Authors: Kulig, Paulina, Musiol, Stephanie, Freiberger, Sandra Nicole, Schreiner, Bettina, Gyülveszi, Gabor, Russo, Giancarlo, Pantelyushin, Stanislav, Kishihara, Kenji, Alessandrini, Francesca, Kündig, Thomas, Sallusto, Federica, Hofbauer, Günther F.L., Haak, Stefan, Becher, Burkhard
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.11.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 14; 38/39; 631/250/127/1213; 64/60; 692/699/249/2510/1758; 82/29; 82/51; 9/10; 96/31; Aminoquinolines - pharmacology; Aminoquinolines - therapeutic use; Animals; Cytokines; Dendritic cells; Female; Humanities and Social Sciences; Humans; Immunology; Inflammation - complications; Inflammation - drug therapy; Inflammation - pathology; Inflammation - prevention & control; Interleukin-12 - metabolism; Interleukin-23 - metabolism; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - pathology; Lymphocytes; Mice, Inbred C57BL; Monoclonal antibodies; multidisciplinary; Neutralization; Pathogenesis; Psoriasis; Psoriasis - complications; Psoriasis - drug therapy; Psoriasis - pathology; Psoriasis - prevention & control; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Science; Science (multidisciplinary); Skin - drug effects; Skin - pathology; Skin diseases; Switzerland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13466

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis. IL-12 and IL-23 share the common p40 subunit yet have distinct immunological functions with IL-12 typically contributing to Th1 responses and IL-23 to Th17 responses. Here the authors show that current p40 based therapies for psoriasis are counterproductive owing to an IFN-γ-independent tissue protective function of IL-12 in skin.