The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice

We showed previously that Lyn is a substrate for caspases, a family of cysteine proteases, involved in the regulation of apoptosis and inflammation. Here, we report that expression of the caspase-cleaved form of Lyn (Lyn Delta N), in mice, mediates a chronic inflammatory syndrome resembling human psoriasis. Genetic ablation of TNF receptor 1 in a LynDN background rescues a normal phenotype, indicating that LynDN mice phenotype is TNF-alpha-dependent. The predominant role of T cells in the disease occurring in LynDN mice was highlighted by the distinct improvement of LynDN mice phenotype in a Rag1-deficient background. Using pan-genomic profiling, we also established that LynDN mice show an increased expression of STAT-3 and inhibitory members of the NF kappa B pathway. Accordingly, LynDN alters NF kappa B activity underlying a link between inhibition of NF kappa B and LynDN mice phenotype. Finally, analysis of Lyn expression in human skin biopsies of psoriatic patients led to the detection of Lyn cleavage product whose expression correlates with the activation of caspase 1. Our data identify a new role for Lyn as a regulator of psoriasis through its cleavage by caspases. The EMBO Journal (2009) 28, 2449-2460. doi:10.1038/emboj.2009.183; Published online 9 July 2009