In conclusion, our study provides novel mechanistic insights into the mesenchymal-specific role of the IKK2 and Ripk3 axes during TNF-dependent arthritogenesis, offering ex vivo and in vivo evidence on their complementary functions in regulating differential modes of pro-inflammatory synovial cell activation and death with significant impact on the physiological outcome in modelled arthritis. Here, RIPK3 is linked to Arthritis.