Activation of canonical inflammasome complex by acute silica exposure in experimental rat model

Abstract

Silicosis is a chronic irreversible pulmonary disease caused by the inhalation of silica crystals in occupational settings in most cases. Persistent inflammation in the alveolar space is considered to be the major reason for tissue damage and lung fibrogenesis. The mechanisms by which silica exposure activates immune cells are not well understood. Here, we employed an in vivo silicosis disease model by intratracheal instillation of a large dose of silica suspension in rats and explored the involvement of inflammasome activation. Marked leukocyte infiltration and edema were observed 3 days following silica exposure in treated animals compared to controls. Using this model, we compared the expression of inflammasome sensors (AIM2 and NLRP3) and effector protein (caspase-1) by western blot and immunohistochemical staining using the lung homogenates and lung tissue sections. Our results demonstrated that following acute silica exposure, AIM2, NLRP3 and caspase-1 expressions were increased in macrophages or/and lung epithelial cells compared to control animals. We also analyzed interleukin 1β expression using lung homogenates, and significant increase in interleukin 1β was observed in 3-day silica-exposed rats. The activation of inflammasome sensors AIM2 and NLRP3 suggested to us that blocking these activators may attenuate silica-associated tissue damage and inflammation.

C/EBPβ Promotes LPS-Induced IL-1β Transcription and Secretion in Alveolar Macrophages via NOD2 Signaling

“…They discovered that AIM2 activation is critical in silica’s ability to stimulate lung immune cells. 40 We found that LPS increased AIM2 expression compared to the control group. C/EBPβ knockdown suppressed AIM2 transcription.…”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…Lysosomal acidification could play a pivotal role, as suggested by a study that showed that H + ATPase inhibitor bafilomycin A impedes activation stimulated by particulate matter [ 84 ]. This finding is further justified by the fact that the MSU can activate the inflammasome as it is responsible for the lysosomal acid environment leading to a massive propagation of Na + , resulting in an increased influx of water and cellular osmolarity and a reduction of the concentration of K + inside the cell [ 85 ].…”

“…Current evidence claims that cathepsin B, a molecule released by lysosomes, contributes to the activation of inflammasome as it is necessary for the release of IL-1β. Furthermore, it was found that inflammasome is not activated in macrophages as a result of particulate exposure if they are treated with a chemical inhibitor for cathepsin B called CA-074-Me [ 84 ].…”

Preliminary Study on the Effect and Molecular Mechanism of Tetrandrine in Alleviating Pulmonary Inflammation and Fibrosis Induced by Silicon Dioxide

“…Subsequently, the ingested SiO 2 particles are released and reintroduced by other macrophages, thus amplifying the vicious cycle of inflammation and cell death [ 6 ]. Depending on the duration of exposure to SiO 2 particles, silicosis can be subdivided into an acute inflammatory form characterized by silicosis deposition disorder and a chronic form characterized by pulmonary collagen deposition and pulmonary fibrotic remodeling [ 7 , 8 ]. In order to reduce the morbidity and mortality associated with irreversible progressive and incurable silicosis, new therapies are urgently needed to prevent long-term inflammation and collagen deposition in silicosis [ 1 ].…”