SignificanceThe mechanisms underlying inflammatory disorders are poorly understood. In this study, we show that inappropriate cell death may cause uncontrolled inflammation. We found that CYLD, an enzyme that removes K63-linked polyubiquitination, is normally inhibited. But in thecpdmmouse strain that has a loss-of-function in theSharpingene, the brake on CYLD is no longer present. When CYLD is no longer inhibited, it turns on death signaling in cells exposed to the cytokine TNF, and the ensuing inappropriate cell death causes skin inflammation and other immune disorders in thecpdmmouse. Removing CYLD from thecpdmmouse prevents cell death and reverses the inflammation. We conclude that excessive CYLD activity leads to inappropriate cell death and inflammation.