The C-terminal acidic tail is responsible for the inhibitory effects of HMGB1 on efferocytosis
The C-terminal acidic tail is responsible for the inhibitory effects of HMGB1 on efferocytosis
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DOI：
10.1189/jlb.0510262
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发表时间：
2010-11-01
影响因子：
5.5
通讯作者：
Abraham, Edward
中科院分区：
文献类型：
--
作者：
Banerjee, Sami;Friggeri, Arnaud;Abraham, Edward
HMGB1最初被描述为参与DNA结合和转录调控的核蛋白。然而，HMGB1也具有细胞外作用，作为一种有效的炎症介质，可以减少吞噬细胞对凋亡细胞的摄取，这一过程被称为efferocytosis。为了探索HMGB1抑制efferocytosis能力的机制，我们研究了c端酸性尾的作用，这是HMGB1的一个区域，已被证明参与特定的分子内相互作用。c端尾部的缺失使HMGB1减少小鼠巨噬细胞摄取凋亡中性粒细胞和减少巨噬细胞吞噬诱导的Erk和Rac-1活化的能力丧失。我们发现RAGE在efferocytosis中起主要作用，并且HMGB1的c端尾部的缺失阻止了HMGB1与RAGE的结合，而不是与参与efferocytosis的其他巨噬细胞受体(如α （V) β(3)整合素）的结合。尽管HMGB1在体内条件下显著减少小鼠肺内肺泡巨噬细胞对凋亡中性粒细胞的摄取，但当HMGB1中c端酸性尾缺失时，这种作用就消失了。这些结果表明，在体外和体内条件下，HMGB1 c端尾部对凋亡中性粒细胞吞噬的抑制作用是由HMGB1 c端尾部负责的。j . Leukoc。生物学杂志。88:973-979；2010.
HMGB1 was described originally as a nuclear protein involved in DNA binding and transcriptional regulation. However, HMGB1 also has an extracellular role as a potent mediator of inflammation and can diminish the uptake of apoptotic cells by phagocytes, a process called efferocytosis. To explore the mechanism responsible for the ability of HMGB1 to inhibit efferocytosis, we examined the role of the C-terminal acidic tail, a region of HMGB1 that has been shown to participate in specific intramolecular interactions. Deletion of the C-terminal tail abrogated the ability of HMGB1 to decrease murine macrophage ingestion of apoptotic neutrophils and to diminish phagocytosis-induced activation of Erk and Rac-1 in macrophages. We found that RAGE plays a major role in efferocytosis, and deletion of the C-terminal tail of HMGB1 prevented binding of HMGB1 to RAGE but not to other macrophage receptors involved in efferocytosis, such as the alpha(V)beta(3) integrin. Whereas HMGB1 decreased ingestion of apoptotic neutrophils significantly by alveolar macrophages under in vivo conditions in the lungs of mice, this effect was lost when the C-terminal acidic tail was absent from HMGB1. These results demonstrate that the HMGB1 C-terminal tail is responsible for the inhibitory effects of HMGB1 on phagocytosis of apoptotic neutrophils under in vitro and in vivo conditions. J. Leukoc. Biol. 88: 973-979; 2010.