During the reporting period, we studied the role of Z-nucleic acid sensing by ZBP1 in the regulation of necroptosis and inflammation. We found that mutation of the Z domains of ZBP1, which are the protein domains sensing Z-nucleic acids, prevented skin inflammation in mouse models with mutations in the protein kinase RIPK1. In addition, we identified a previously unknown function of ZBP1 in triggering intestinal epithelial cell death and causing intestinal inflammation by sensing Z-nucleic acids. 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 Z domains and this is necessary for the activation of 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. Moreover, 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 addition, we could show that sensing of Z-nucleic acids by ZBP1 induces the activation of RIPK3 and the phosphorylation of its substrate MLKL within the nucleus, resulting in necroptosis. 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 triggering necroptosis, resulting in the pathogenesis of chronic inflammatory pathologies.