Inflammasomes are protein complexes that secrete interleukin (IL)-1and IL-18. Unlike in Cryopyrin- Associated Autoinflammatory Syndromes (CAPS), the immune mechanisms and cell types promoting destructive autoinflammation in patients with gain-of-function mutations in the inflammasome adaptor NLRC4 (NLRC4-AID) are unknown. Initial studies suggest anti-IL-1 therapies to be ineffective, and showed high circulating levels of IL-18 in NLRC4-AID patients. We hypothesize that NLRC4-AID is primarily caused by excessive activation of the IL-18/IFN immune axis in myeloid cells, Natural killer (NK) and T cells. To empirically address the cell types and immune mechanisms involved in NLRC4- AID, an novel in vivo mouse model of NLRC4-AID was generated by exchanging the evolutionary conserved Val341 residue in mouse NLRC4 for a disease-associated alanine. Detailed analysis of NLRC4 expression, combined with in vivo and ex vivo characterization of the cell types and deregulated immune pathways will lead to a better understanding of the (patho)physiological roles and signaling pathways controlled by NLRC4. In addition, we will identify and functionally characterize novel disease-associated mutations in autoinflammatory patients with high circulating IL-18. This project will significantly increase insight in autoinflammatory mechanisms, and may lead to the development of innovative diagnostics and therapeutics targeting IL-18-driven inflammatory disease.