石棉是恶性间皮瘤的主要原因。之前的研究发现，石棉诱导的间皮瘤与HMGB1从细胞核释放到细胞质，从细胞质释放到细胞外空间有关。在细胞质中，HMGB1促进自噬，影响了石棉诱导的细胞死亡。在细胞外，HMGB1刺激了TNFα的分泌。这两种细胞因子共同启动了一种慢性炎症过程，随着时间的推移促进了间皮瘤的发展。研究尚未解决的问题是，细胞外HMGB1的主要来源是间皮细胞、炎症细胞还是两者都有。这些信息对于确定目标并设计干预石棉诱导的间皮瘤的预防/治疗策略至关重要。为了解决这个问题，我们开发了条件性间皮HMGB1敲除（Hmgb1ΔpMeso）和条件性骨髓单核细胞系HMGB1敲除（Hmgb1ΔMylc）小鼠模型。我们在这里证实，HMGB1在石棉暴露后的早期炎症阶段主要由间皮细胞产生和释放。间皮细胞释放的HMGB1导致非典型间皮细胞增生，并在某些动物中逐年发展为间皮瘤。我们发现，无法产生HMGB1的Hmgb1ΔpMeso小鼠对石棉表现出极大减少的炎症反应，其间皮细胞表达和分泌的TNFα水平显著降低。此外，石棉沉积区域的组织微环境中，M1极化的巨噬细胞比M2巨噬细胞的比例增加。支持这些发现的生物学意义是，Hmgb1ΔpMeso小鼠间皮瘤的发生率和特异性存活率延迟且降低了。总之，我们的研究为HMGB1作为石棉诱导的间皮瘤的驱动因子提供了一个生物学解释。

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.