Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Saleh, Danish UNSPECIFIED UNSPECIFIED UNSPECIFIED Najjar, Malek UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Shah, Saumil UNSPECIFIED UNSPECIFIED UNSPECIFIED Nogusa, Shoko UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Paczosa, Michelle K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gough, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertin, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Whalen, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Fitzgerald, Katherine A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Slavov, Nikolai UNSPECIFIED orcid.org/0000-0003-2035-1820 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Balachandran, Siddharth UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelliher, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Mecsas, Joan UNSPECIFIED UNSPECIFIED UNSPECIFIED Degterev, Alexei UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language NF-KAPPA-B; INNATE IMMUNE-RESPONSES; MIXED LINEAGE KINASE; CELL-DEATH; PROGRAMMED NECROSIS; III SECRETION; ADAPTER TRIF; TNF-ALPHA; YERSINIA-PSEUDOTUBERCULOSIS; SIGNALING PATHWAY Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23002