Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813.
Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2307999120. doi: 10.1073/pnas.2307999120. Epub 2023 Sep 20.
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 . 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 () and the conditional myelomonocytic-lineage HMGB1-knockout () 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 , 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 . 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, 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.
石棉是恶性间皮瘤的主要原因。先前的研究将石棉诱导的间皮瘤与 HMGB1 从核内到细胞质以及从细胞质到细胞外空间的释放联系起来。在细胞质中，HMGB1 诱导自噬，从而损害石棉诱导的细胞死亡。细胞外，HMGB1 刺激细胞因子的分泌。这两种细胞因子共同启动慢性炎症过程，随着时间的推移促进间皮瘤的发展。细胞外 HMGB1 的主要来源是间皮细胞、炎症细胞还是两者兼而有之，这一点尚未解决。这些信息对于确定靶点和设计预防/治疗策略以干扰石棉诱导的间皮瘤至关重要。为了解决这个问题，我们开发了条件性间皮 HMGB1 敲除（）和条件性骨髓单核细胞系 HMGB1 敲除（）小鼠模型。我们在这里确定 HMGB1 主要是由暴露于石棉后炎症早期的间皮细胞产生和释放的。HMGB1 从间皮细胞中的释放导致非典型间皮细胞增生，并且在一些动物中，这些增生在数年内演变为间皮瘤。我们发现，其间皮细胞不能产生 HMGB1，对石棉的炎症反应大大降低，其间皮细胞表达和分泌的水平显著降低。此外，与 M2 巨噬细胞相比，在石棉沉积物区域的组织微环境中，M1 极化的巨噬细胞比例增加。这些发现的生物学意义得到了支持，HMGB1 敲除小鼠显示出间皮瘤的发生率降低和间皮瘤特异性生存率增加。总的来说，我们的研究为 HMGB1 作为石棉诱导的间皮瘤的驱动因素提供了生物学解释。
