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Acute Silica Exposure Triggers Pulmonary Inflammation Through Macrophage Pyroptosis: An Experimental Simulation
Haoyu Yin1,2, Lei Fang2, Lifeng Wang1
1Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Shandong University, Jinan, China.
Abstract:
Silica is an essential substrate of various materials, and inhaling silica induces pulmonary diseases potentially associated with macrophage pyroptosis. Utilizing silica of micro- and nano- sizes, we explored the role of macrophage pyroptosis in silica-induced pulmonary inflammation. Under the transmission electron microscopy, we found that the internalization of silica nanoparticle induced membrane rupture and increased the number of intracellular vacuoles, and both sizes of silica could suppress cell viability and proliferation. Also, silica-exposed macrophages generated higher levels of ROS, together with the upregulated expression of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, and IL-6. However, the expression of these proteins was suppressed after removing ROS or NLRP3. In addition, we found increased expression of TLR4 and NF-κB responsible for silica recognition and pyroptosis priming after silica exposure. For in vivo studies, we established animal model by intratracheally instilling 5 mg of silica into mice with/without NLRP3 inhibition. Four weeks later, we found diffused infiltration of inflammatory cells and enhanced collagen hyperplasia partially reversed by additional treatment with MCC950, so as the expression of pyroptotic molecules and proinflammatory cytokines. In particular, the dual immunofluorescent staining showed co-expression of macrophage-specific biomarker F4/80 and NLRP3 within the cells, and silica of nano-size showed more potent toxicity and pathogenicity than that of the micro-sized particles both in vitro and in vivo. To sum up, macrophage pyroptosis is an upstream event of silica-induced pulmonary inflammation promoted by ROS through the TLR4/NLRP3/NF-κB signaling axis.
Insights
Inhaling silica triggers lung inflammation via macrophage pyroptosis, a process involving reactive oxygen species (ROS) and the NLRP3 inflammasome. Nanoparticle silica exhibits greater toxicity, highlighting pyroptosis as a key therapeutic target for silica-induced lung disease.
Area of Science:
- Pulmonary Medicine
- Immunology
- Toxicology
Background:
- Silica inhalation is linked to pulmonary diseases, with macrophage pyroptosis implicated in the inflammatory response.
- Understanding the mechanisms of silica-induced lung inflammation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of macrophage pyroptosis in silica-induced pulmonary inflammation.
- To explore the signaling pathways involved in silica-induced pyroptosis and inflammation.
- To compare the effects of micro- and nano-sized silica particles on lung inflammation.
Main Methods:
- In vitro studies using silica-exposed macrophages to assess cell viability, pyroptosis markers (NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-6), and reactive oxygen species (ROS) production.
- In vivo studies using a mouse model of silica-induced lung inflammation, with and without NLRP3 inhibition (MCC950).
- Transmission electron microscopy and dual immunofluorescence staining (F4/80) were employed.
Main Results:
- Silica exposure suppressed cell viability and proliferation, induced ROS production, and upregulated key pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-6).
- ROS and NLRP3 inhibition mitigated pyroptosis marker expression. TLR4 and NF-κB were upregulated, indicating their role in silica recognition and pyroptosis.
- In vivo, silica induced inflammatory cell infiltration and collagen deposition, partially reversed by MCC950. Nano-silica showed greater toxicity and pathogenicity than micro-silica.
Conclusions:
- Macrophage pyroptosis is an upstream event in silica-induced pulmonary inflammation, mediated by ROS via the TLR4/NLRP3/NF-κB signaling axis.
- Targeting NLRP3 inflammasome activation presents a potential therapeutic strategy for silica-induced lung diseases.
- Nano-sized silica particles pose a more significant threat due to their enhanced toxicity and pathogenicity.
