NLRP3 deficiency abrogates silica-induced neutrophil infiltration, pulmonary damage and fibrosis

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 contributi...

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Published in:Respiratory research Vol. 26; no. 1; pp. 109 - 17
Main Authors: Lam, Maggie, Barry, Kristian T., Hodges, Christopher J., Harpur, Christopher M., Ong, James D. H., Rosli, Sarah, West, Alison C., Dousha, Lovisa, Hertzog, Paul J., Mansell, Ashley, Tate, Michelle D.
Format: Journal Article
Language:English
Published: London BioMed Central 21.03.2025
BioMed Central Ltd
Nature Publishing Group
BMC
Subjects:
Actin
Animals
Cell activation
Complications and side effects
Damage
Development and progression
Elastase
Fibrosis
Growth factors
Health aspects
Histopathology
In vivo methods and tests
Infiltration
Inflammasomes
Inflammasomes - metabolism
Inflammation
Intranasal administration
Lasers
Leukocytes (neutrophilic)
Lung - drug effects
Lung - immunology
Lung - metabolism
Lung - pathology
Lung diseases
Lung nodules
Medicine
Medicine & Public Health
Mice
Mice, Inbred C57BL
Mice, Knockout
Mouse model
Neutrophil Infiltration - drug effects
Neutrophil Infiltration - physiology
Neutrophils
NLR Family, Pyrin Domain-Containing 3 Protein - deficiency
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLRP3
NLRP3 inflammasome
Nodules
Occupational diseases
Pathogenesis
Pneumology/Respiratory System
Protein expression
Proteins
Pulmonary fibrosis
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - genetics
Pulmonary Fibrosis - metabolism
Pulmonary Fibrosis - pathology
Pulmonary Fibrosis - prevention & control
Silica
Silica dust
Silicon dioxide
Silicon Dioxide - administration & dosage
Silicon Dioxide - toxicity
Silicosis
Silicosis - genetics
Silicosis - metabolism
Silicosis - pathology
Smooth muscle
Stem cells
Australia
United States > US
Mouse model
Inflammation
NLRP3 inflammasome
Silicosis
Fibrosis
ISSN:1465-993X, 1465-9921, 1465-993X
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Summary: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.
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ISSN:1465-993X
1465-9921
1465-993X
DOI:10.1186/s12931-025-03192-y