Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-β Synthesis Induced by Lipopolysaccharide

• Published in: The Journal of immunology (1950) 2017-06, Vol.198 (11), p.4435-4447
• Main Authors: Saleh, Danish, Najjar, Malek, Zelic, Matija, Shah, Saumil, Nogusa, Shoko, Polykratis, Apostolos, Paczosa, Michelle K, Gough, Peter J, Bertin, John, Whalen, Michael, Fitzgerald, Katherine A, Slavov, Nikolai, Pasparakis, Manolis, Balachandran, Siddharth, Kelliher, Michelle, Mecsas, Joan, Degterev, Alexei
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - immunology; Bacteria; Bone marrow; Catalytic activity; Cytokines; Gram-negative bacteria; Gram-Negative Bacteria - immunology; Homology; Immune response; Inflammation; Innate immunity; Interferon; Interferon-beta - biosynthesis; Interferon-beta - immunology; Klebsiella; Klebsiella - immunology; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophages; Macrophages - immunology; Macrophages - microbiology; Mice; Necroptosis; Necrosis - immunology; Pathogens; Phosphorylation; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Serine; Threonine; TLR4 protein; Toll-Like Receptor 4 - immunology; Toll-like receptors; Virulence factors; Yersinia; Yersinia - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601717

The innate immune response is a central element of the initial defense against bacterial and viral pathogens. Macrophages are key innate immune cells that upon encountering pathogen-associated molecular patterns respond by producing cytokines, including IFN-β. In this study, we identify a novel role for RIPK1 and RIPK3, a pair of homologous serine/threonine kinases previously implicated in the regulation of necroptosis and pathologic tissue injury, in directing IFN-β production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-β synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-β production may be elicited in an analogous fashion using LPS in bone marrow-derived macrophages upon inhibition of caspases. Notably, this regulation requires kinase activities of both RIPK1 and RIPK3, but not the necroptosis effector protein, MLKL. Mechanistically, we provide evidence that necrosome-like RIPK1 and RIPK3 aggregates facilitate canonical TRIF-dependent IFN-β production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-β is markedly induced by avirulent strains of Gram-negative bacteria, and , and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-β during the host inflammatory responses to bacterial infection and suggest that the axis in which these kinases operate may represent a target for bacterial virulence factors.