Saleh, Danish, Najjar, Malek, Zelic, Matija, Shah, Saumil, Nogusa, Shoko, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Paczosa, Michelle K., Gough, Peter J., Bertin, John, Whalen, Michael, Fitzgerald, Katherine A., Slavov, Nikolai ORCID: 0000-0003-2035-1820, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Balachandran, Siddharth, Kelliher, Michelle, Mecsas, Joan and Degterev, Alexei (2017). Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-beta Synthesis Induced by Lipopolysaccharide. J. Immunol., 198 (11). S. 4435 - 4448. BETHESDA: AMER ASSOC IMMUNOLOGISTS. ISSN 1550-6606

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Saleh, DanishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Najjar, MalekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zelic, MatijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, SaumilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogusa, ShokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polykratis, ApostolosUNSPECIFIEDorcid.org/0000-0001-6720-3302UNSPECIFIED
Paczosa, Michelle K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gough, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertin, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whalen, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fitzgerald, Katherine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slavov, NikolaiUNSPECIFIEDorcid.org/0000-0003-2035-1820UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Balachandran, SiddharthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelliher, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mecsas, JoanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degterev, AlexeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-230020
DOI: 10.4049/jimmunol.1601717
Journal or Publication Title: J. Immunol.
Volume: 198
Number: 11
Page Range: S. 4435 - 4448
Date: 2017
Publisher: AMER ASSOC IMMUNOLOGISTS
Place of Publication: BETHESDA
ISSN: 1550-6606
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; INNATE IMMUNE-RESPONSES; MIXED LINEAGE KINASE; CELL-DEATH; PROGRAMMED NECROSIS; III SECRETION; ADAPTER TRIF; TNF-ALPHA; YERSINIA-PSEUDOTUBERCULOSIS; SIGNALING PATHWAYMultiple languages
ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23002

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