During the reporting period, we studied how Z-nucleic acids may be implicated in the pathogenesis of inflammatory conditions. In particular, we focused on the role of Z-nucleic acid sensing by ZBP1 in the regulation of cell death and inflammation in vivo in mouse models of inflammatory diseases. We could show that ZBP1 is activated by binding to endogenous Z-nucleic acids and triggers keratinocyte necroptosis and inflammation in mice lacking RIPK1 in the epidermis or expressing RIPK1 with mutated RIP homotypic interaction motif (RHIM). In addition, we found that Z-nucleic acid-induced ZBP1-mediated necroptosis is under negative regulation by caspase-8 and that inhibition of caspase-8 triggers ZBP1-dependent inflammation in the intestine. These results provided the first experimental evidence that sensing of endogenous Z-nucleic acids by ZBP1 causes inflammation in vivo in relevant models of inflammatory diseases. Furthermore, we found that ZBP1 binds cellular dsRNA via its Zα domains, identifying endogenous Z-RNA as a key ligand triggering ZBP1-mediated necroptosis. Computational analysis revealed that endogenous retroelement-derived transcripts constitute the majority of putatively dsRNA species in mouse skin, suggesting that endogenous retroelement-derived Z-RNA is the most likely ligand activating ZBP1 in vivo. Furthermore, we could show that ZBP1 acts in a Zα domain-dependent manner to induce the activation of RIPK3 and its substrate MLKL within the nucleus, suggesting that sensing of nuclear Z-RNA provides a potent trigger activating ZBP1-mediated cell death. Collectively, the results obtained during the first period of the project revealed an important role of ZBP1 in sensing endogenous Z-RNA likely derived from endogenous retroelements and inducing necroptosis and inflammation, which is relevant for the better understanding of the mechanisms controlling the pathogenesis of chronic inflammatory diseases.