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 (LynΔN), in mice, mediates a chronic inflammatory syndrome resembling human psoriasis. Genetic ablation of TNF receptor 1 in a LynΔN background rescues a normal phenotype, indicating that LynΔN mice phenotype is TNF‐α‐dependent. The predominant role of T cells in the disease occurring in LynΔN mice was highlighted by the distinct improvement of LynΔN mice phenotype in a Rag1‐deficient background. Using pan‐genomic profiling, we also established that LynΔN mice show an increased expression of STAT‐3 and inhibitory members of the NFκB pathway. Accordingly, LynΔN alters NFκB activity underlying a link between inhibition of NFκB and LynΔN 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.