Epigenetic Modulation in Septic Immunosuppression

项目总结 败血症免疫抑制的一个特征是由于淋巴细胞减少而导致淋巴细胞数量减少 增殖和细胞死亡增加。淋巴细胞计数低，称为淋巴细胞减少症，突出表明 细菌清除率低的脓毒症患者的预后和院内感染和死亡。 表观遗传学调节染色质结构以调节免疫。尽管它很重要，但它的作用 败血症免疫抑制的表观遗传学在淋巴细胞减少方面仍然难以捉摸。在这份提案中，我们确定 细菌升高的精氨酸N-甲基转移酶4/辅活化子相关精氨酸 甲基转移酶1(PRMT4/CARM1)是脓毒症中淋巴细胞减少的关键；PRMT4的耗尽或抑制 PRMT4可减轻细菌介导的淋巴细胞在细胞和小鼠模型中的死亡。我们的预赛 研究表明，细菌在蛋白水平上增加了小鼠和人淋巴细胞中的PRMT4。细菌减少 E3泛素连接酶SCF-FBXO9促进PRMT4蛋白在细胞中的稳定性和丰度，从而导致 淋巴细胞死亡。耗尽PRMT4或用小分子抑制PRMT4减少细菌介导的 细胞和小鼠败血症模型中的淋巴细胞死亡。这些发现显示了一个未被描述的关键角色 染色质调节剂PRMT4在淋巴细胞死亡中的作用可能为脓毒症的治疗开辟新的途径 免疫抑制。因此，我们的中心假设是细菌上调了PRMT4蛋白，抑制了它 SCF-Fbxo9介导的蛋白酶体降解导致大量淋巴细胞死亡 免疫抑制；因此，抑制PRMT4可以减轻细菌介导的脓毒症淋巴细胞死亡 免疫抑制。为了探索这一假说，我们提出了以下目标：(I)确定细菌 衍生内毒素通过降低E3泛素连接酶SCF-Fbxo9来提高PRMT4蛋白水平；以及(Ii) 研究PRMT4升高是否会导致大量淋巴细胞死亡，从而减弱对PRMT4的抑制 细菌引起的败血症免疫抑制。这些研究将确立A细胞的病理生理功能 染色质调节剂PRMT4在脓毒症淋巴细胞死亡中的作用这些研究将扩大 为我们理解表观遗传调控如何在发病机制中发挥核心作用奠定了概念基础 败血症免疫抑制。这些研究可能最终会成为翻译方法的跳板 使用小分子疗法来靶向这种免疫调节剂。

Project summary A hallmark of septic immunosuppression is a reduced number of lymphocytes due to decreased lymphocyte proliferation and increased cell death. A low lymphocyte count referred to as lymphopenia underscores a poor prognosis for septic patients with lower bacterial clearance and second nosocomial infections and death. Epigenetics modulates chromatin architecture to regulate immunity. Despite its importance, the role of epigenetics in septic immunosuppression in terms of lymphopenia remains elusive. In this proposal, we identify that bacteria-elevated Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) is critical for lymphopenia in sepsis; depletion of PRMT4 or inhibition of PRMT4 may attenuate the bacteria-mediated lymphocyte death in cellular and mice models. Our preliminary study shows that bacteria increase PRMT4 at protein level in murine and human lymphocytes. Bacteria reduce an E3 ubiquitin ligase SCF-FBXO9 to promote PRMT4 protein stability and abundance in the cells that leads to lymphocyte death. Depletion of PRMT4 or inhibition of PRMT4 with small molecule reduces bacteria mediated lymphocyte death in cellular and mice septic models. These findings demonstrate an un-described role of a key chromatin modulator PRMT4 in lymphocyte death that may shed lights on novel therapeutic avenue in septic immunosuppression. Therefore, our central hypothesis is that bacteria elevates PRMT4 protein inhibiting its SCF-Fbxo9 mediated proteasomal degradation that causes substantial lymphocyte death to lead immunosuppression; thus inhibition of PRMT4 may attenuate bacteria-mediated lymphocyte death in septic immuno-suppression. To explore this hypothesis we propose the following aims: (i) to determine if bacteria derived endotoxin LPS elevates PRMT4 protein levels by reducing an E3 ubiquitin ligase SCF-Fbxo9; and (ii) to study if elevated PRMT4 leads to substantial lymphocyte death thereby inhibition of PRMT4 may attenuate bacteria-induced septic immunosuppression. These studies will establish the pathophysiological function of a chromatin modulator, PRMT4, as a new effector in lymphocyte death in sepsis. These studies will expand the conceptual groundwork for us to understand how epigenetic regulation plays a central role in the pathogenesis of septic immunosuppression. These studies may serve as a springboard for translational approaches eventually using small molecule therapeutics to target this immune modulator.