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Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.
Pubmed ID: 30612879 RIS Download
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View all literature mentionsCell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line THP-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionslaboratory mouse with name C57BL/6N-Irgm1em1(IMPC)Wtsi/Wtsi from MGI.
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View all literature mentionsThis monoclonal targets Genetic locus: RELA (human) mapping to 11q13.1; Rela (mouse) mapping to 19 A.
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View all literature mentionsThis monoclonal targets Atg7 (D12B11) Rabbit mAb
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View all literature mentionsThis monoclonal targets beta Actin
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View all literature mentionsThis polyclonal targets p38 MAPK, phospho (Thr180 / Tyr182)
View all literature mentionsThis polyclonal targets Goat polyclonal Secondary to Rabbit IgG - H&L (HRP)
View all literature mentionsThis monoclonal targets p62 Lck Ligand
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