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Article RIPK1 and RIPK3 Kinases Promote Cell-Death- Independent In?ammation by Toll-like Receptor

4 Graphical Abstract Highlights d RIPK1 and RIPK3 kinases promote TRIF-dependent cytokine production by LPS in vitro d RIPK1 and RIPK3 kinase-dependent in?ammation is independent of cell death d Erk1/2 mediates RIPK1 and RIPK3 kinase dependent in?ammation d RIPK1 kinase and RIPK3 are mediators of LPS-induced cytokine production in vivo Authors Malek Najjar, Danish Saleh, Matija Zelic, .

.., Michelle Kelliher, Alexander Poltorak, Alexei Degterev Correspondence [email protected] In Brief Kinase activities of RIPK1 and RIPK3 are critical for necroptotic cell death. Degterev and colleagues demonstrate that RIPK1 and RIPK3 kinases also direct in?ammatory gene expression induced by Toll-like receptor

4 ligand, lipopolysaccharide, in vitro, and in vivo. This regulation is independent of necroptosis and requires Erk1/2, cFos, and NF-kB. Accession Numbers GSE72797 GSE73836 Najjar et al., 2016, Immunity 45, 46C59 July 19,

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2016 Elsevier Inc. http://dx.doi.org/10.1016/j.immuni.2016.06.007 Immunity Article RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent In?ammation by Toll-like Receptor

4 Malek Najjar,1,10 Danish Saleh,2,10 Matija Zelic,3 Shoko Nogusa,4 Saumil Shah,5 Albert Tai,6 Joshua N. Finger,7 Apostolos Polykratis,8 Peter J. Gough,7 John Bertin,7 Michael J. Whalen,9 Manolis Pasparakis,8 Siddharth Balachandran,4 Michelle Kelliher,3 Alexander Poltorak,6 and Alexei Degterev1,5,* 1Program in Pharmacology and Experimental Therapeutics, Sackler Graduate School, Tufts University, Boston, MA 02111, USA 2Medical Scientist Training Program and Program in Neuroscience, Sackler Graduate School, Tufts University, Boston, MA 02111, USA 3Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 4Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 5Department of Developmental, Molecular &

Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA 6Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA 7Pattern Recognition Receptor Discovery Performance Unit, Immuno-In?ammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA 8Institute for Genetics, Center for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne,

50674 Cologne, Germany 9Neuroscience Center and Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA 10Co-?rst author *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2016.06.007 SUMMARY Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic in?ammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activa- tion of necroptotic death. In this study, we have described roles for these kinases as master regula- tors of pro-in?ammatory gene expression induced by lipopolysaccharide, independent of their well- documented cell death functions. In primary macro- phages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained acti- vation of Erk, cFos, and NF-kB, which were required for in?ammatory changes. Utilizing genetic and phar- macologic tools, we showed that RIPK1 and RIPK3 account for acute in?ammatory responses induced by lipopolysaccharide in vivo;