Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis.
Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis.
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脓毒症的一个标志是淋巴细胞数量减少，称为淋巴细胞减少症，其发生于淋巴细胞增殖减少或细胞死亡增加，导致免疫抑制。组蛋白修饰酶通过其表观遗传和非表观遗传功能调节免疫;然而，这些酶在淋巴细胞减少症中的作用仍然是难以捉摸的。我们使用分子生物学方法来研究染色质调节蛋白精氨酸N-甲基转移酶4（PRMT 4）/辅激活因子相关精氨酸甲基转移酶1在脓毒症患者和细胞及动物脓毒症模型的人类样本中的高表达和功能。我们确定PRMT 4在脓毒症患者和实验性脓毒症中全身性升高。革兰氏阴性菌及其衍生的内毒素脂多糖（LPS）增加了B和T淋巴细胞以及THP-1单核细胞中的PRMT 4。单细胞RNA测序结果表明活化的T淋巴细胞中PRMT 4基因表达增加。增强的PRMT 4对于诱导淋巴细胞凋亡至关重要，但对单核细胞THP-1细胞则不然。PRMT 4蛋白的异位表达通过半胱天冬酶3介导的细胞死亡信号传导引起大量淋巴细胞死亡，并且PRMT 4的敲除废除了LPS介导的淋巴细胞死亡。用小分子化合物抑制PRMT 4减弱脓毒症的互补模型中的淋巴细胞死亡。这些研究结果表明，以前未表征的作用，一个关键的染色质调节淋巴细胞的存活，可能揭示设计治疗方式，以减轻脓毒性免疫抑制的严重程度。
One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive. We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models. We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.
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影响因子：
2.6
作者：
Cheng H;Qin Y;Fan H;Su P;Zhang X;Zhang H;Zhou G
通讯作者：
Zhou G
DOI：
10.1038/nri3552
发表时间：
2013-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.8
作者：
Nielsen, JS;Larsson, A;Tonnesen, E
通讯作者：
Tonnesen, E
影响因子：
4.6
作者：
O'Brien, Karen B.;Alberich-Jorda, Meritxell;Kobayashi, Susumu
通讯作者：
Kobayashi, Susumu
影响因子：
16
作者：
Cheng, Donghang;Cote, Jocelyn;Bedford, Mark T.
通讯作者：
Bedford, Mark T.