Journal article
Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease
The Journal of experimental medicine, Vol.217(3), e20191644
03/01/2020
DOI: 10.1084/jem.20191644
PMCID: PMC7062518
PMID: 31869420
Abstract
RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity-independent necroptosis driven by the RIPK3-MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3-caspase-8 signaling axis-driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity-independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.
Details
- Title: Subtitle
- Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease
- Creators
- R. K. Subbarao Malireddi - St. Jude Children's Research HospitalPrajwal Gurung - St. Jude Children's Research HospitalSannula Kesavardhana - St. Jude Children's Research HospitalParimal Samir - St. Jude Children's Research HospitalAmanda Burton - St. Jude Children's Research HospitalHarisankeerth Mummareddy - St. Jude Children's Research HospitalPeter Vogel - St. Jude Children's Research HospitalStephane Pelletier - St. Jude Children's Research HospitalSandeepta Burgula - Osmania UniversityThirumala-Devi Kanneganti - St. Jude Children's Research Hospital
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.217(3), e20191644
- DOI
- 10.1084/jem.20191644
- PMID
- 31869420
- PMCID
- PMC7062518
- NLM abbreviation
- J Exp Med
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Publisher
- Rockefeller Univ Press
- Number of pages
- 13
- Grant note
- K22AI127836 / National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30ES005605 / National Institute of Environmental Health Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) AI101935; AI124346; AR056296; CA163507 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA University of Iowa startup funds American Lebanese Syrian Associated Charities; American Lebanese Syrian Associated Charities (ALSAC)
- Language
- English
- Date published
- 03/01/2020
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984359765802771
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