Journal
IMMUNITY
Volume 43, Issue 2, Pages 264-276Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.07.018
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Funding
- NIH [GM071723, HL097183, AI082406, AI099009, AI120625, AR064349, AR057532, AR066739, AR050250, AR054796, AI092490, HL108795, AR061593, AI52430, T32AR007611]
- Cancer Center Support Grant [CA060553]
- Skin Disease Research Center [AR057216]
- American Heart Association [13GRNT17110117, 11POST585000]
- ATS/Scleroderma Foundation
- British Heart Foundation [RG/10/15/28578]
- Solovy/Arthritis Research Society
- Northwestern University Transgenic and Targeted Mutagenesis Laboratory
- Mouse Histology and Phenotyping Laboratory
- British Heart Foundation [RG/10/15/28578] Funding Source: researchfish
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In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1 beta and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial for the maintenance of homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1 beta and IL-18 release, pyroptosis, and the release of ASC particles. There is no mouse ortholog for POP1, but transgenic expression of human POP1 in monocytes, macrophages, and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation, and ASC danger particles. POP1 expression was regulated by TLR and IL-1R signaling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.
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