Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells

Abstract

BackgroundPleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear.ResultsWe document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model.ConclusionsThese novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.

Targeting the epigenome in malignant pleural mesothelioma

“…Indeed, given the relatively low mutational burden of mesotheliomas (3) Whereas accumulating evidence indicates recurrent hypermethylation of tumor suppressor genes in MPM, the mechanisms underlying this phenomenon as yet have not been elucidated. Cytokine signaling can modulate DNMT expression and mediate hypermethylation of target genes in colorectal carcinoma and erythroleukemia cells (45,46); conceivably, cytokines induced by high mobility group box 1 (HMGB1) or the NLRP3 inflammasome in response to asbestos exposure dysregulate expression and/ or targeting of DNMTs and other components of the DNA methylation machinery during evolution of MPM (47)(48)(49)(50). Recently we performed qRT-PCR analysis of a panel of genes encoding epigenetic regulators in a panel of cultured cell lines derived from asbestos associated MPM relative to either LP-9 (a commercially available normal mesothelial cell line) or a normal mesothelial line established in our laboratory.…”

Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome

“…11 Fibers were sterilized and suspended as previously described. 6 Cell Treatments with Asbestos, IL-1b, or the IL-1 Receptor Antagonist…”

“…6 All cells were grown to 90% to 95% confluency. All experiments were repeated at least twice or more.…”

“…6 In these cells, however, the activation of the inflammasome is protracted, leading to the accumulation of IL-1b and IL-18. 6 IL-1b signaling up-regulates the secretion of the cytokines IL-6 and IL-8, which play a major role in lung fibrosis.…”

“…6 In these cells, however, the activation of the inflammasome is protracted, leading to the accumulation of IL-1b and IL-18. 6 IL-1b signaling up-regulates the secretion of the cytokines IL-6 and IL-8, which play a major role in lung fibrosis. 7 In addition to promoting fibrosis, IL-1b induces epithelial to mesenchymal transition (EMT) in corneal endothelial cells and induces stemness in colon cancer cells through the activation of transcription factors that regulate the mesenchymal phenotype.…”