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Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis

机译：高迁移率的第1框巨噬细胞内吞会触发细胞凋亡

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摘要

Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9. Pyroptosis is a caspase-1-dependent programmed cell death, which features rapid plasma membrane rupture, DNA fragmentation, and release of proinflammatory intracellular contents. Pyroptosis can be triggered by various stimuli, however, the mechanism underlying pyroptosis remains unclear. In this study, we identify a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrate that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces cell pyroptosis. The endocytosis of HMGB1 triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. These findings shed light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury.
机译：巨噬细胞可以由高度保守的核蛋白高迁移率族盒1（HMGB1）激活和调节。 HMGB1的炎症功能是通过与细胞表面受体结合而介导的，包括晚期糖基化终产物（RAGE），Toll样受体（TLR）2，TLR4和TLR9受体。细胞凋亡是一种依赖caspase-1的程序性细胞死亡，其特征在于快速的质膜破裂，DNA断裂和促炎性细胞内内容物释放。细胞凋亡可以通过各种刺激来触发，但是，细胞凋亡的机制尚不清楚。在这项研究中，我们确定了HMGB1诱导巨噬细胞发烧的新途径。我们证明，HMGB1，通过RAGE和动力蛋白依赖性信号传导，启动HMGB1内吞作用，进而诱导细胞凋亡。 HMGB1的内吞作用触发了一系列分子事件，包括组织蛋白酶B从破裂的溶酶体中释放出来，随后形成了pyptotosome和caspase-1激活。我们进一步证实内毒素血症期间HMGB1诱导的巨噬细胞发烧也发生在体内，这提示这种形式的发烧在炎症发展中的病理生理意义。这些发现揭示了配体-受体内在化在指导细胞命运中的调节作用，这在感染和损伤后炎症的进展中可能具有重要作用。

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