Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Najjar, Malek UNSPECIFIED UNSPECIFIED UNSPECIFIED Saleh, Danish UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Nogusa, Shoko UNSPECIFIED UNSPECIFIED UNSPECIFIED Shah, Saumil UNSPECIFIED UNSPECIFIED UNSPECIFIED Tai, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Finger, Joshua N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Gough, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertin, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Whalen, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Balachandran, Siddharth UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelliher, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Poltorak, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Degterev, Alexei UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	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 KAPPA-B ACTIVATION; PROGRAMMED NECROSIS; TRANSFORMING ACTIVITY; TNF-ALPHA; C-FOS; NECROPTOSIS; APOPTOSIS; PHOSPHORYLATION; TRIF; INHIBITOR Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26979