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

Abstract

Despite the causal relationship established between malignant mesothelioma (MM) and asbestos exposure, the exact mechanism by which asbestos induces this neoplasm and other asbestos-related diseases is still not well understood. MM is characterized by chronic inflammation, which is believed to play an intrinsic role in the origin of this disease. We recently found that asbestos activates the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in a protracted manner, leading to an up-regulation of IL-1b and IL-18 production in human mesothelial cells. Combined with biopersistence of asbestos fibers, we hypothesize that this creates an environment of chronic IL-1b signaling in human mesothelial cells, which may promote mesothelial to fibroblastic transition (MFT) in an NLRP3-dependent manner. Using a series of experiments, we found that asbestos induces a fibroblastic transition of mesothelial cells with a gain of mesenchymal markers (vimentin and N-cadherin), whereas epithelial markers, such as E-cadherin, are down-regulated. Use of siRNA against NLRP3, recombinant IL-1b, and IL-1 receptor antagonist confirmed the role of NLRP3 inflammasomeedependent IL-1b in the process. In vivo studies using wild-type and various inflammasome component knockout mice also revealed the process of asbestos-induced mesothelial to fibroblastic transition and its amelioration in caspase-1 knockout mice. Taken together, our data are the first to suggest that asbestos induces mesothelial to fibroblastic transition in an inflammasome-dependent manner. (Am J Pathol 2017, 187: 665e678; http://dx

Synthetic hydrosilicate nanotubes induce low pro‐inflammatory and cytotoxic responses compared to natural chrysotile in lung cell cultures

“…17 Furthermore, asbestos has been shown to activate secretion of IL-1β via an inflammasome-mediated mechanism in macrophages. 15,18 TGF-β is a growth factor, known to be involved in pathological development, including fibrosis, via recruitment of macrophages and fibroblasts, fibroblast proliferation and transformation of epithelial cells to fibroblasts (epithelial-mesenchymal transition, EMT). 16 In vivo studies show that TGF-β is important in asbestos-and CNT-induced lung fibrosis.…”

Exosomes from asbestos‐exposed cells modulate gene expression in mesothelial cells

“…This is interesting given that thrombospondin-1 has been identified as being significantly overexpressed in MM tumors (24). We were also intrigued to see that proteomics analysis indicated higher exosomal abundances of vimentin upon producer cell exposure to asbestos because vimentin is a key regulator in the response to asbestos exposure by regulating the NLRP3 inflammasome and is used as a mesenchymal marker in the transition of mesothelial cells to a more neoplastic state (23,25). In addition, we validated the increased exosomal abundance of glypican-1 in exosomes from asbestos-exposed cells, which piqued our interest because of its established role as an exosomal indicator of cancer, most notably as a pancreatic cancer biomarker exosome (12,26).…”

“…Effect of BEAS2B exosomes on mesothelial cells was analyzed by PCR Array using epithelial-to-mesenchymal transition (EMT) template (Qiagen) to assess the gene expression patterns of genes (23).…”

“…Validation of expression changes in selected genes of interest (related to asbestos exposure and/or cancer) was conducted by quantitative RT-PCR after cDNA synthesis from 1 mg RNA by reverse transcription with AMV Reverse Transcriptase (Promega, Madison, WI, USA), according to the manufacturer's protocol (23). We used Assays on Demand primers and probes for E-cadherin, IL-1ra, desmoplakin, cyclin B2 (CCNB2), early growth response1 (EGR1), Franconi anemia complementation group D2 (FANCD2), ER oxidoreductase-b (ERO1B), cysteine rich with EGF-like domains 2 (CRELD2), and jagged 1 (JAG1) (Thermo Fisher Scientific).…”

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.…”