Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
"G. Scansetti" Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Turin, 10125 Turin, Italy.
Int J Mol Sci. 2023 Oct 13;24(20):15145. doi: 10.3390/ijms242015145.
While exposure to long amphibolic asbestos fibers (L > 10 µm) results in the development of severe diseases including inflammation, fibrosis, and mesothelioma, the pathogenic activity associated with short fibers (L < 5 µm) is less clear. By exposing murine macrophages to short (SFA) or long (LFA) fibers of amosite asbestos different in size and surface chemistry, we observed that SFA internalization resulted in pyroptotic-related immunogenic cell death (ICD) characterized by the release of the pro-inflammatory damage signal (DAMP) IL-1α after inflammasome activation and gasdermin D (GSDMD)-pore formation. In contrast, macrophage responses to non-internalizable LFA were associated with tumor necrosis factor alpha (TNF-α) release, caspase-3 and -7 activation, and apoptosis. SFA effects exclusively resulted from Toll-like receptor 4 (TLR4), a pattern-recognition receptor (PRR) recognized for its ability to sense particles, while the response to LFA was elicited by a multifactorial ignition system involving the macrophage receptor with collagenous structure (SR-A6 or MARCO), reactive oxygen species (ROS) cascade, and TLR4. Our findings indicate that asbestos fiber size and surface features play major roles in modulating ICD and inflammatory pathways. They also suggest that SFA are biologically reactive in vitro and, therefore, their inflammatory and toxic effects in vivo should not be underestimated.
虽然暴露于长的 Amphibolic 石棉纤维（L > 10 µm）会导致严重的疾病，包括炎症、纤维化和间皮瘤，但与短纤维（L < 5 µm）相关的致病活性尚不明确。通过将短纤维（SFA）或长纤维（LFA）暴露于大小和表面化学性质不同的铁石棉石棉中，我们观察到 SFA 的内化导致与细胞焦亡相关的免疫原性细胞死亡（ICD），其特征是在炎症小体激活和gasdermin D（GSDMD）-孔形成后释放促炎损伤信号（DAMP）IL-1α。相比之下，巨噬细胞对不可内化的 LFA 的反应与肿瘤坏死因子 alpha（TNF-α）的释放、半胱天冬酶-3 和 -7 的激活以及细胞凋亡有关。SFA 的作用仅来自 Toll 样受体 4（TLR4），作为一种能够识别颗粒的模式识别受体（PRR），而对 LFA 的反应则是由多因素点火系统引起的，该系统涉及具有胶原结构的巨噬细胞受体（SR-A6 或 MARCO）、活性氧（ROS）级联反应和 TLR4。我们的研究结果表明，石棉纤维的大小和表面特征在调节 ICD 和炎症途径方面起着重要作用。它们还表明，SFA 在体外具有生物反应性，因此不应低估其在体内的炎症和毒性作用。
