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- W4313385478 abstract "Abstract Macrophage activation syndrome (MAS) is a life-threatening sepsis-like hyperinflammatory state arising in certain infectious and rheumatic diseases. Previous genetic associations have implicated genes critical for perforin-mediated cytotoxicity. However, we recently identified that activating mutations in inflammasome component NLRC4 lead to MAS and early-onset enterocolitis. Patients with NLRC4-MAS also have chronically and extraordinarily elevated serum IL-18. Notably, disease-causing mutations in other inflammasomes do not cause MAS or chronic IL-18 elevation. In vitro, IL-1b production by THP1 cells expressing various NLRC4 patient mutations correlated with disease severity and identified pathogenic clusters in the molecular structure. To further study the function of NLRC4, we created a mouse bearing the T337S point mutation. Like NLRC4-MAS patients, NLRC4-T337S mice demonstrate elevated serum IL-18 in the absence of systemic inflammation. However, macrophages from NLRC4-T337S mice did not demonstrate enhanced IL-1β or IL-18 production. Correspondingly, bone marrow chimeras demonstrated that IL-18 hyperproduction was derived from non-hematopoietic cells. NLRC4-T337S mice did not demonstrate more severe disease in response to repeated systemic stimulation through TLR9 or TLR4, nor upon LCMV infection, but developed colitis with IL-10 receptor blockade. These results suggest intestinal epithelia, which express both NLRC4 and proIL-18, may be a source of pathogenic IL-18 in this model. Future work will clarify the source(s) of excessive IL-18 and identify how chronic IL-18 effects on gut homeostasis and T and NK cell responses may promote systemic hyperinflammation." @default.
- W4313385478 created "2023-01-06" @default.
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- W4313385478 date "2016-05-01" @default.
- W4313385478 modified "2023-09-25" @default.
- W4313385478 title "An Nlrc4 mutation associated with systemic hyperinflammation drives spontaneous non-hematopoietic IL-18 hyperproduction" @default.
- W4313385478 doi "https://doi.org/10.4049/jimmunol.196.supp.62.10" @default.
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