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Saleh D , Najjar M , Zelic M , Shah S , Nogusa S , Polykratis A , Paczosa MK , Gough PJ , Bertin J , Whalen M , Fitzgerald KA , Slavov N , Pasparakis M , Balachandran S , Kelliher M , Mecsas J , Degterev A
Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-beta Synthesis Induced by Lipopolysaccharide
J Immunol. 2017 Jun 01;198(11) :4435-4447
PMID: 28461567    PMCID: PMC5471631    URL: https://www.ncbi.nlm.nih.gov/pubmed/28461567
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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-beta. 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-beta production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-beta synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-beta 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-beta production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-beta is markedly induced by avirulent strains of Gram-negative bacteria, Yersinia and Klebsiella, and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-beta 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.
1550-6606 Saleh, Danish Najjar, Malek Zelic, Matija Shah, Saumil Nogusa, Shoko Polykratis, Apostolos ORCID: http://orcid.org/0000-0001-6720-3302 Paczosa, Michelle K Gough, Peter J ORCID: http://orcid.org/0000-0002-5110-9300 Bertin, John Whalen, Michael Fitzgerald, Katherine A Slavov, Nikolai ORCID: http://orcid.org/0000-0003-2035-1820 Pasparakis, Manolis Balachandran, Siddharth Kelliher, Michelle ORCID: http://orcid.org/0000-0001-9211-3659 Mecsas, Joan Degterev, Alexei Journal Article United States J Immunol. 2017 Jun 1;198(11):4435-4447. doi: 10.4049/jimmunol.1601717. Epub 2017 May 1.