Abstract
The inflammasome NLRP6 plays a crucial role in regulating inflammation and host defense against microorganisms in the intestine. However, the molecular mechanisms by which NLRP6 function is inhibited to prevent excessive inflammation remain unclear. Here, we demonstrate that the deubiquitinase Cyld prevents excessive interleukin 18 (IL-18) production in the colonic mucosa by deubiquitinating NLRP6. We show that deubiquitination inhibited the NLRP6-ASC inflammasome complex and regulated the maturation of IL-18. Cyld deficiency in mice resulted in elevated levels of active IL-18 and severe colonic inflammation following Citrobacter rodentium infection. Further, in patients with ulcerative colitis, the concentration of active IL-18 was inversely correlated with CYLD expression. Thus, we have identified a novel regulatory mechanism that inhibits the NLRP6-IL-18 pathway in intestinal inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Citrobacter rodentium
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Deubiquitinating Enzyme CYLD / genetics
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Deubiquitinating Enzyme CYLD / metabolism*
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Disease Models, Animal
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Disease Susceptibility
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Enterobacteriaceae Infections / immunology
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Enterobacteriaceae Infections / metabolism
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Enterobacteriaceae Infections / microbiology
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Enterobacteriaceae Infections / pathology
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Enterocolitis / etiology*
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Enterocolitis / metabolism*
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Enterocolitis / pathology
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Gene Expression
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Humans
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Inflammasomes / metabolism*
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Interleukin-18 / antagonists & inhibitors
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Interleukin-18 / metabolism*
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Mice
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Mice, Knockout
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Protein Binding / immunology
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Receptors, Cell Surface / metabolism*
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Ubiquitination
Substances
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Inflammasomes
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Interleukin-18
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Nod-like receptor pyrin domain-containing protein 6, mouse
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Receptors, Cell Surface
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Deubiquitinating Enzyme CYLD