Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo

• Published in: The Journal of immunology (1950) 2014-08, Vol.193 (4), p.1539-1543
• Main Authors: Polykratis, Apostolos, Hermance, Nicole, Zelic, Matija, Roderick, Justine, Kim, Chun, Van, Trieu-My, Lee, Thomas H, Chan, Francis K M, Pasparakis, Manolis, Kelliher, Michelle A
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - immunology; Animals; Apoptosis - drug effects; Apoptosis - immunology; Cells, Cultured; Gene Knock-In Techniques; Hypothermia - chemically induced; Hypothermia - mortality; Inflammation - genetics; Inflammation - immunology; Macrophages - immunology; MAP Kinase Signaling System - immunology; Mice; Mice, Inbred C57BL; Necrosis - chemically induced; Necrosis - immunology; NF-kappa B - immunology; Poly I-C - pharmacology; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - immunology; Receptors, Tumor Necrosis Factor, Type I - immunology; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - pharmacology; Vaccinia - immunology; Vaccinia virus; Vaccinia virus - growth & development; Vaccinia virus - immunology; Virus Replication - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400590

The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFκB and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro-reconstitution studies suggested that RIPK1 displays distinct kinase activity-dependent and -independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1(-/-) mice, which die shortly after birth, Ripk1(D138N/D138N) mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid-induced necroptosis in vitro, and Ripk1(D138N/D138N) mice are protected from TNF-induced shock in vivo. Moreover, Ripk1(D138N/D138N) mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis.