The interplay of IKK, NF‐κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation

Summary Regulated cell death pathways have important functions in host defense and tissue homeostasis. Studies in genetic mouse models provided evidence that cell death could cause inflammation in different tissues. Inhibition of RIPK 3‐ MLKL ‐dependent necroptosis by FADD and caspase‐8 was identified as a key mechanism preventing inflammation in epithelial barriers. Moreover, the interplay between IKK / NF ‐κB and RIPK 1 signaling was recognized as a critical determinant of tissue homeostasis and inflammation. NEMO was shown to regulate RIPK 1 kinase activity‐mediated apoptosis by NF ‐κB‐dependent and –independent functions, which are critical for averting chronic tissue injury and inflammation in the intestine and the liver. In addition, RIPK 1 was shown to exhibit kinase activity‐independent functions that are essential for preventing cell death, maintaining tissue architecture and inhibiting inflammation. In the intestine, RIPK 1 acts as a scaffold to prevent epithelial cell apoptosis and preserve tissue integrity. In the skin, RIPK 1 functions via its RHIM to counteract ZBP 1/ DAI ‐dependent activation of RIPK 3‐ MLKL ‐dependent necroptosis and inflammation. Collectively, these studies provided evidence that the regulation of cell death signaling plays an important role in the maintenance of tissue homeostasis, and suggested that cell death could be causally involved in the pathogenesis of inflammatory diseases.