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Title
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The autoinflammation-associated mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice
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Author
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Abstract
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| Background: Autoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood.Methods: Here, we developed and characterized a novel genetic mouse model expressing a murine version of the AIFEC-associated NLRC4(V341A) mutation from its endogenous Nlrc4 genomic locus.Results: NLRC4(V341A) expression in mice recapitulated increased circulating IL-18 levels as observed in AIFEC patients. Housing NLRC4(V341A)-expressing mice in germfree (GF) conditions showed that these systemic IL-18 levels were independent of the microbiota, and unmasked an additional IL-18-inducing effect of NLRC4(V341A )expression in the intestines. Remarkably, elevated IL-18 levels did not provoke detectable intestinal pathologies in NLRC4(V341A)-expressing mice, even not upon genetically ablating IL-18 binding protein (IL-18BP), which is an endogenous IL-18 inhibitor that has been used therapeutically in AIFEC. In addition, NLRC4(V341A) expression did not alter susceptibility to the NLRC4-activating gastrointestinal pathogens Salmonella Typhimurium and Citrobacter rodentium.Conclusion: As observed in AIFEC patients, mice expressing a murine NLRC4(V341A) mutant show elevated systemic IL-18 levels, suggesting that the molecular mechanisms by which this NLRC4(V341A) mutant induces excessive IL-18 production are conserved between humans and mice. However, while our GF and infection experiments argue against a role for commensal or pathogenic bacteria, identifying the triggers and mechanisms that synergize with IL-18 to drive NLRC4(V341A)-associated pathologies will require further research in this NLRC4(V341A) mouse model. |
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Language
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English
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Source (journal)
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Frontiers in immunology. - Place of publication unknown
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Publication
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Place of publication unknown
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2023
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ISSN
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1664-3224
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DOI
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10.3389/FIMMU.2023.1272639
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Volume/pages
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14
(2023)
, p. 1-14
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Article Reference
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1272639
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ISI
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001123549000001
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Pubmed ID
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38090573
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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