| First Author | Thompson JK | Year | 2017 |
| Journal | Am J Pathol | Volume | 187 |
| Issue | 3 | Pages | 665-678 |
| PubMed ID | 28056339 | Mgi Jnum | J:240171 |
| Mgi Id | MGI:5882617 | Doi | 10.1016/j.ajpath.2016.11.008 |
| Citation | Thompson JK, et al. (2017) Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome. Am J Pathol 187(3):665-678 |
| abstractText | 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-1beta and IL-18 production in human mesothelial cells. Combined with biopersistence of asbestos fibers, we hypothesize that this creates an environment of chronic IL-1beta 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-1beta, and IL-1 receptor antagonist confirmed the role of NLRP3 inflammasome-dependent IL-1beta 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. |
