Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation

Abstract

Asbestos carcinogenesis has been linked to the release of cytokines and mutagenic reactive oxygen species (ROS) from inflammatory cells. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. We show that asbestos-induced HM cell death is a regulated form of necrosis that links to carcinogenesis. Asbestos-exposed HM activate poly(ADP-ribose) polymerase, secrete H 2 O 2 , deplete ATP, and translocate high-mobility group box 1 protein (HMGB1) from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-α, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. In both mice and hamsters injected with asbestos, HMGB1 was specifically detected in the nuclei, cytoplasm, and extracellular space of mesothelial and inflammatory cells around asbestos deposits. TNF-α was coexpressed in the same areas. HMGB1 levels in asbestos-exposed individuals were significantly higher than in nonexposed controls (P < 0.0001). Our findings identify the release of HMGB1 as a critical initial step in the pathogenesis of asbestos-related disease, and provide mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response, and especially blocking HMGB1, may decrease the risk of malignant mesothelioma among asbestos-exposed cohorts.mesothelioma | tumor necrosis factor-alpha | carcinogenesis | biomarker | chemoprevention

The Role of Inflammation in Development and Therapy of Malignant Mesothelioma

“…Further studies in human mesothelial cells confirmed that asbestos exposure caused priming of NLRP3 (increased mRNA levels) as well as its activation (Shukla et al, 2003;2011). In support of our work, Yang et al (2010) showed the release of high mobility group box-1 protein (HMGB-1) from asbestosexposed mesothelial cells (Yang et al, 2010). The release of HMGB-1 may possibly occur via inflammasome-induced pyroptosis, an inflammation-mediated cell death process dependent on inflammsome activation of caspase-1.…”

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

“…HMGB1 contributes to the development of malignant mesotheliomain response to the exposure of mesothelial cells to asbestos. 31,32 Conversely viable mesothelioma cells actively secrete HMGB1: interference with HMGB1 or with the RAGE receptors limits the growth of human xenografts in immunodeficient mice, 33 supporting the contention that the molecule can play cancer-supporting actions in the extracellular environment. 34 Cell death occurring after chemotherapy with cytotoxic agents substantially increases the extent of HMGB1 released from MC-38 cells.…”

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…The doses of the compounds and recombinants were selected based on previous reports. 20,49 Eyes that sustained marked surgical trauma (for example, retinal or subretinal hemorrhage, bacterial infection) were excluded from further analyses.…”