Najjar, Malek, Saleh, Danish, Zelic, Matija, Nogusa, Shoko, Shah, Saumil, Tai, Albert, Finger, Joshua N., Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Gough, Peter J., Bertin, John, Whalen, Michael J., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Balachandran, Siddharth, Kelliher, Michelle, Poltorak, Alexander and Degterev, Alexei (2016). RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4. Immunity, 45 (1). S. 46 - 60. CAMBRIDGE: CELL PRESS. ISSN 1097-4180

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Abstract

Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, 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 activation of Erk, cFos, and NF-kappa B, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Najjar, MalekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saleh, DanishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zelic, MatijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogusa, ShokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, SaumilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tai, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finger, Joshua N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polykratis, ApostolosUNSPECIFIEDorcid.org/0000-0001-6720-3302UNSPECIFIED
Gough, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertin, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whalen, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Balachandran, SiddharthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelliher, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poltorak, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degterev, AlexeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-269795
DOI: 10.1016/j.immuni.2016.06.007
Journal or Publication Title: Immunity
Volume: 45
Number: 1
Page Range: S. 46 - 60
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4180
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
KAPPA-B ACTIVATION; PROGRAMMED NECROSIS; TRANSFORMING ACTIVITY; TNF-ALPHA; C-FOS; NECROPTOSIS; APOPTOSIS; PHOSPHORYLATION; TRIF; INHIBITORMultiple languages
ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26979

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