HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma

Our plain-English summary of HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma, by J.S. Suarez, F. Novelli, K. Goto, et al (Proceedings of the National Academy of Sciences of the United States of America, 2023).

The study

• Authors: J.S. Suarez, F. Novelli, K. Goto, M. Ehara, M. Steele, J.H. Kim, A.A. Zolondick, J. Xue, R. Xu, M. Saito, S. Pastorino, M. Minaai, Y. Takanishi, M. Emi, I. Pagano, A. Wakeham, T. Berger, H.I. Pass, G. Gaudino, T.W. Mak, M. Carbone, H. Yang
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2023;120(39):e2307999120
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

In plain English

This was an animal experiment in mice. The authors used two conditional HMGB1-knockout strains, one lacking HMGB1 in mesothelial cells (Hmgb1ΔpMeso) and one lacking it in myelomonocytic-lineage cells (Hmgb1ΔMylc), compared with control strains that included Hmgb1+/+, floxed Hmgb1f/f, Wt1CreERT2/+-Hmgb1+/+ and LysMCre/+-Hmgb1+/+ mice. All groups received 0.5 mg crocidolite asbestos by intraperitoneal injection once a week for 10 weeks (13 mice per group for the short-term study, 40 per group for the long-term study). In culture, mesothelial cells from Hmgb1ΔpMeso mice exposed to crocidolite showed more micronuclei (P less than 0.05) and more released nucleosomes (P less than 0.01) but much less TNFα than wild-type cells. One week after the last injection, Hmgb1ΔpMeso mice had smaller granulomas (P less than 0.01), more CD86+ (M1) and fewer CD206+ (M2) macrophages, fewer neutrophils, and less HMGB1 in peritoneal lavage; Hmgb1ΔMylc mice showed no statistically significant difference in lavage HMGB1 compared with their controls. Over 21 months, 21/33 (63.6%) Hmgb1ΔpMeso mice developed mesothelioma versus 31/32 (96.9%), 38/40 (95.0%) and 21/24 (87.5%) in three control groups, with longer mesothelioma-specific survival (median 450 d; P = 0.0162).

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment in genetically engineered mice (in vivo short-term and long-term asbestos injection studies, with in vitro work on mouse mesothelial cells)
• Who was studied: Conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mice, aged 8 to 12 weeks, with control strains Hmgb1+/+, Hmgb1f/f, Wt1CreERT2/+-Hmgb1+/+ and LysMCre/+-Hmgb1+/+; 13 mice per group for the short-term inflammation study and 40 per group for the long-term tumour study; experiments done under University of Hawaii animal care approval
• Exposure: Crocidolite asbestos, 0.5 mg per mouse injected intraperitoneally once a week for 10 weeks (5 mg total in the long-term experiment); cultured mesothelial cells were treated with 5 micrograms per square centimetre crocidolite
• Main results:
  • Cultured mesothelial cells from Hmgb1ΔpMeso mice exposed to crocidolite had significantly more micronuclei than wild-type cells (P less than 0.05)
  • The same Hmgb1ΔpMeso mesothelial cells released more histone H3 and nucleosomes (P less than 0.01) but secreted much less TNFα than wild-type cells, with reduced TNFα and TNFRI mRNA
  • In Hmgb1ΔpMeso mice, granulomas forming around asbestos deposits were significantly smaller than in wild-type controls (P less than 0.01)
  • Diaphragm biopsies from Hmgb1ΔpMeso mice showed more M1 (CD86+) and fewer M2 (CD206+) macrophages than controls
  • Peritoneal lavage HMGB1 was lower in Hmgb1ΔpMeso mice than wild-type (P less than 0.01), while for Hmgb1ΔMylc mice no significant difference from their controls was observed at that time point
  • Peritoneal Ly6G+ neutrophils were fewer in Hmgb1ΔpMeso mice than wild-type controls: 2.4 ± 0.96 × 10^5 cells versus 3.8 ± 0.66 × 10^5 (P = 0.0301)
  • Mesothelioma incidence over the long-term experiment: 21/33 (63.6%) in Hmgb1ΔpMeso mice versus 31/32 (96.9%) WT, 38/40 (95.0%) Hmgb1f/f and 21/24 (87.5%) Wt1CreERT2/+ controls (P less than 0.0001)
  • Hmgb1ΔpMeso mice had longer mesothelioma-specific survival (median 450 days; P = 0.0162) than the three control groups
  • The Hmgb1ΔMylc long-term arm was stopped at 11 months because 36/40 mice had died of infection, peritonitis and intestinal occlusion; 7/40 had developed mesothelioma at necropsy
  • Serum HMGB1 was lower in Hmgb1ΔpMeso mice than controls during the first 3 months after the asbestos injections (P less than 0.05), but not at 6 and 9 months
• The authors' conclusion: The authors concluded that HMGB1 released by mesothelial cells into the microenvironment is crucial for asbestos-induced mesothelioma development and is the main target for therapies aimed at the early steps of the process
• Limitations the authors state:
  • The authors state the Hmgb1ΔMylc mice could be followed only briefly because they were vulnerable to bacterial infection and most died within a year, preventing a full comparison with Hmgb1ΔpMeso mice
  • The authors state that the thiol (redox) modifications of HMGB1 in the asbestos-induced inflammatory microenvironment could not be predicted and are left for future study

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Mesothelial Cells, Mesothelioma, Malignant Mesothelioma, Cytokine, Inflammation, Asbestos Exposure, Atypical Mesothelial Proliferation.

Related studies

• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation — H. Yang, Z. Rivera, et al. (2010)
• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)
• Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma — S. Jube, Z.S. Rivera, et al. (2012)

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