Journal article
TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation
The Journal of experimental medicine, Vol.215(4), pp.1023-1034
04/02/2018
DOI: 10.1084/jem.20171922
PMCID: PMC5881469
PMID: 29500178
Abstract
The NOD-like receptor (NLR)–P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-β activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis. Autocrine tumor necrosis factor (TNF) signaling in the absence of TAK1 induced spontaneous RIPK1-dependent NLRP3 inflammasome activation and cell death. We further showed that TAK1 suppressed homeostatic NF-κB and extracellular signal–related kinase (ERK) activation to limit spontaneous TNF production. Moreover, the spontaneous inflammation resulting from TAK1-deficient macrophages drives myeloid proliferation in mice, and was rescued by RIPK1 deficiency. Overall, these studies identify a critical role for TAK1 in maintaining NLRP3 inflammasome quiescence and preserving cellular homeostasis and survival.
Details
- Title: Subtitle
- TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation
- Creators
- R.K. Subbarao Malireddi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TNPrajwal Gurung - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TNJayadev Mavuluri - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TNTejasvi Krishna Dasari - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TNJeffery M Klco - Department of Pathology, St. Jude Children's Research Hospital, Memphis, TNHongbo Chi - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TNThirumala-Devi Kanneganti - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.215(4), pp.1023-1034
- DOI
- 10.1084/jem.20171922
- PMID
- 29500178
- PMCID
- PMC5881469
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: CA163507, AR056296, AI124346, AI101935; DOI: 10.13039/100012524, name: American Lebanese Syrian Associated Charities
- Language
- English
- Date published
- 04/02/2018
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094615402771
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