Maggie Lam, Kristian T Barry, Christopher J Hodges, Christopher M Harpur, James D H Ong, Sarah Rosli, Alison C West, Lovisa Dousha, Paul J Hertzog, Ashley Mansell, Michelle D Tate
{"title":"NLRP3 deficiency abrogates silica-induced neutrophil infiltration, pulmonary damage and fibrosis.","authors":"Maggie Lam, Kristian T Barry, Christopher J Hodges, Christopher M Harpur, James D H Ong, Sarah Rosli, Alison C West, Lovisa Dousha, Paul J Hertzog, Ashley Mansell, Michelle D Tate","doi":"10.1186/s12931-025-03192-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Silicosis is a progressive and often fatal occupational lung disease. The NLRP3 inflammasome is an innate immune sensor that is activated by silica. Accumulating evidence has implicated a role for NLRP3 in silicosis pathogenesis. In this study, we mechanistically elucidated the contribution of NLRP3 to silica-induced pulmonary disease.</p><p><strong>Methods: </strong>The in vivo role of NLRP3 was investigated following intranasal delivery of 2 mg of silica or diluent alone to wildtype, NLRP3 reporter, and NLRP3-deficient mice. Protein expression, inflammation, and histopathology were analyzed in the lung.</p><p><strong>Results: </strong>Intranasal administration of silica recapitulated the key pathological features of human silicosis, including nonresolving inflammation, the formation of silicotic nodules, and diffuse lung fibrosis. A reporter mouse placed under the native NLRP3 promoter revealed silica rapidly upregulated NLRP3 expression throughout the lung. NLRP3-deficient mice displayed marked early reductions in silica-induced IL-1β and IL-18 levels in the airways. Additionally, NLRP3 deficiency impaired the rapid infiltration of conventional Siglec-F<sup>-</sup> and fibrotic Siglec-F<sup>+</sup> neutrophils, which correlated with reduced levels of neutrophil elastase. Deficiency in acute NLRP3-mediated inflammation correlated with significantly reduced pulmonary transforming growth factor beta and alpha smooth muscle actin expression, tissue damage, and fibrosis in the chronic phase of disease progression. Importantly, this included reduced silicotic nodule size and cellularity.</p><p><strong>Conclusions: </strong>These findings highlight a major detrimental role for the NLRP3 inflammasome in driving silica-induced pulmonary neutrophil infiltration, TGFβ-mediated myofibroblast activation, tissue damage, and fibrosis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"109"},"PeriodicalIF":5.8000,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929224/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12931-025-03192-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Silicosis is a progressive and often fatal occupational lung disease. The NLRP3 inflammasome is an innate immune sensor that is activated by silica. Accumulating evidence has implicated a role for NLRP3 in silicosis pathogenesis. In this study, we mechanistically elucidated the contribution of NLRP3 to silica-induced pulmonary disease.
Methods: The in vivo role of NLRP3 was investigated following intranasal delivery of 2 mg of silica or diluent alone to wildtype, NLRP3 reporter, and NLRP3-deficient mice. Protein expression, inflammation, and histopathology were analyzed in the lung.
Results: Intranasal administration of silica recapitulated the key pathological features of human silicosis, including nonresolving inflammation, the formation of silicotic nodules, and diffuse lung fibrosis. A reporter mouse placed under the native NLRP3 promoter revealed silica rapidly upregulated NLRP3 expression throughout the lung. NLRP3-deficient mice displayed marked early reductions in silica-induced IL-1β and IL-18 levels in the airways. Additionally, NLRP3 deficiency impaired the rapid infiltration of conventional Siglec-F- and fibrotic Siglec-F+ neutrophils, which correlated with reduced levels of neutrophil elastase. Deficiency in acute NLRP3-mediated inflammation correlated with significantly reduced pulmonary transforming growth factor beta and alpha smooth muscle actin expression, tissue damage, and fibrosis in the chronic phase of disease progression. Importantly, this included reduced silicotic nodule size and cellularity.
Conclusions: These findings highlight a major detrimental role for the NLRP3 inflammasome in driving silica-induced pulmonary neutrophil infiltration, TGFβ-mediated myofibroblast activation, tissue damage, and fibrosis.
背景:矽肺是一种进行性且常致死性的职业性肺病。NLRP3炎性小体是一种先天免疫传感器,可被二氧化硅激活。越来越多的证据表明NLRP3在矽肺发病机制中的作用。在这项研究中,我们从机制上阐明了NLRP3在二氧化硅诱导的肺部疾病中的作用。方法:将2 mg二氧化硅或稀释剂单独滴入野生型、NLRP3报告型和NLRP3缺陷型小鼠中,研究NLRP3在体内的作用。分析肺组织蛋白表达、炎症及组织病理学变化。结果:鼻内注射二氧化硅重现了人类矽肺的主要病理特征,包括不溶解性炎症、矽肺结节的形成和弥漫性肺纤维化。放置在天然NLRP3启动子下的报告小鼠显示,二氧化硅迅速上调了NLRP3在整个肺部的表达。nlrp3缺陷小鼠气道中二氧化硅诱导的IL-1β和IL-18水平早期显著降低。此外,NLRP3缺陷会损害常规siglece - f -和纤维化的siglece - f +中性粒细胞的快速浸润,这与中性粒细胞弹性酶水平降低相关。急性nlrp3介导的炎症缺乏与疾病进展慢性期肺转化生长因子β和α平滑肌肌动蛋白表达显著降低、组织损伤和纤维化相关。重要的是,这包括减少硅结节的大小和细胞结构。结论:这些发现强调了NLRP3炎性小体在驱动二氧化硅诱导的肺中性粒细胞浸润、tgf β介导的肌成纤维细胞活化、组织损伤和纤维化中的主要有害作用。
期刊介绍:
Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases.
As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion.
Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.