8 Many studies have shown that pyroptosis is essential for the formulation of lesions and fibrosis of the kidney, liver, and bone, but less research has been done on the lungs. The activated NLRP3 inflammasome further proteolyzes the precursor of Caspase-1, while the cleaved Caspase-1 promotes the maturation and secretion of interleukin-18 (IL-18) and IL-1β and induces pyroptosis of macrophages. 7 For the pathogenesis of silicosis, available evidence suggests that the inhaled SiNPs are first recognized by the pattern recognition receptors (PRRs) on the macrophage, then trigger nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs), mainly NLRP3, and initiate the assembly of the NLRP3 inflammasome, composed of NLRP3, ASC, and Pro-Caspase-1. 6 Studies have shown that macrophage pyroptosis is an indispensable segment of silicosis, an occupational disease induced by long-term silica exposure to large populations worldwide. Macrophages are primary cells in the innate immune system and play essential roles in inflammatory response by releasing cytokines. 3, 4 Recent studies reveal that macrophage pyroptosis, a pro-inflammatory and pro-autolytic programmed cell death, plays a crucial role in the pathogenesis of silica-induced pulmonary inflammation, 5 indicating that in-depth investigation of the mechanism of pyroptosis may contribute to the identification of potential therapeutic targets of related diseases. Unfortunately, the pulmonary damages caused by SiNP exposure are irreversible and have no effective treatments at the current stage. Silica nanoparticle (SiNP), one of the most widely used nanomaterials, is commonly exposed in occupational conditions such as coal mining, metallurgy, and constructions, while long-term inhalation of SiNP can lead to pulmonary inflammation and fibrosis. 1, 2 It has dramatically increased the opportunities for nanoparticle exposure, and the health effects of nanoparticle exposure have also drawn considerable attention. Over the past decades, nanotechnology has achieved rapid development in a broad range of fields like medicine, cosmetics, drug delivery, and imaging. Keywords: silica nanoparticles, NLRP3 inflammasome, cathepsin B, pyroptosis, macrophage Besides, we found SiNP joint treatment with leupeptin, a CTSB inhibitor, could inhibit the expression of CTSB, but it had no effect on the expression of NLRP3, ASC, and Caspase-1, and the process of macrophage pyroptosis was also not affected.Ĭonclusion: SiNP exposure induces rupture of macrophages and the release of lysosomal CTSB, but CTSB fails to specifically act on the NLRP3 inflammasome to induce pyroptosis which is causally linked to lung inflammation and fibrosis. Also, the expression of NLRP3, ASC, Caspase-1, GSDMD, Pro-IL-1β, IL-1β, and CTSB increased under the stimulation of SiNP, which could be suppressed by additional treatment with MCC950, an NLRP3-specific inhibitor. Results: We found that SiNPs internalization caused the rupture of macrophage membrane and promoted the aging of cells with increased intracellular vacuoles. Moreover, Western blot was performed to detect the expression of proteins related to pyroptosis and CTSB after blocking the expression of NLRP3 and CTSB.
The morphological features of SiNPs were exhibited by the SEM and TEM, and the effects of SiNPs’ internalization on macrophages were examined by the TEM and immunofluorescent staining.
Methods: To further characterize the role of CTSB in silica-induced pyroptosis, we conducted this study by establishing SiNP exposure models in vitro. However, mechanisms underlying the activation of NLRP3 signaling are complex, and whether cathepsin B (CTSB), an enzyme released by the ruptured lysosome, could trigger NLRP3 assembly is controversial. Introduction: Silica nanoparticles (SiNPs) are one of the most widely used inorganic nanomaterials, and exposure to SiNP has been demonstrated to induce pulmonary inflammation, primarily promoted by the NLRP3-mediated macrophage pyroptosis. Lan Ma, 1, 2 Zhengpu Han, 1, 2 Haoyu Yin, 1, 2 Jiaqi Tian, 1, 2 Jing Zhang, 3 Ning Li, 3 Chunjie Ding, 4 Lin Zhang 2ġSchool of Public Health, Weifang Medical University, Weifang, 261053, People’s Republic of China 2Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Shandong University, Jinan, 250001, People’s Republic of China 3School of Public Health, North China University of Science and Technology, Tangshan, 063210, People’s Republic of China 4School of Public Health, Xinxiang Medical University, Xinxiang, 453000, People’s Republic of ChinaĬorrespondence: Lin Zhang, Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Shandong University, Jinan, 250001, People’s Republic of China, Tel +85046, Email
0 kommentar(er)
