Inflammasome Genetic Variants, Macrophage Function, and Clinical Outcomes in Cystic Fibrosis.
Inflammasome Genetic Variants, Macrophage Function, and Clinical Outcomes in Cystic Fibrosis.
复制标题
囊性纤维化的炎性体遗传变异、巨噬细胞功能和临床结果。
DOI：
10.1165/rcmb.2020-0257oc
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发表时间：
2021
影响因子：
6.4
通讯作者：
Emond,MaryJ
中科院分区：
文献类型：
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作者：
Graustein,AndrewD;Berrington,WilliamR;Buckingham,KatiJ;Nguyen,FeliciaK;Joudeh,LaraL;Rosenfeld,Margaret;Bamshad,MichaelJ;Gibson,RonaldL;Hawn,ThomasR;Emond,MaryJ
Cystic fibrosis (CF) is characterized by chronic airway infection, inflammation, and tissue damage that lead to progressive respiratory failure. NLRP3 and NLRC4 are cytoplasmic pattern recognition receptors that activate the inflammasome, initiating a caspase-1–mediated response. We hypothesized that gain-of-function inflammasome responses are associated with worse outcomes in children with CF. We genotyped nonsynonymous variants inNLRP3and theNLRC4pathway from individuals in the EPIC (EarlyPseudomonasInfection Control) Observational Study cohort and tested for association with CF outcomes. We generated knockouts ofNLRP3andNLRC4in human macrophage–like cells and rescued knockouts with wild-type or variant forms ofNLRP3andNLRC4. We identified a SNP inNLRP3, p.(Q705K), that was associated with a higher rate ofP. aeruginosacolonization (N= 609;P= 0.01; hazard ratio, 2.3 [Cox model]) and worsened lung function over time as measured by forced expiratory volume in 1 second (N= 445;P= 0.001 [generalized estimating equation]). We identified a SNP inNLRC4, p.(A929S), that was associated with a lower rate ofP. aeruginosacolonization as part of a composite of rare variants (N= 405;P= 0.045; hazard ratio, 0.68 [Cox model]) and that was individually associated with protection from lung function decline (P< 0.001 [generalized estimating equation]). Rescue of theNLRP3knockout with the p.(Q705K) variant produced significantly more IL-1β in response to NLRP3 stimulation than rescue with the wild type (P= 0.020 [Student’sttest]). We identified a subset of children with CF at higher risk of early lung disease progression. Knowledge of these genetic modifiers could guide therapies targeting inflammasome pathways.
