HISTONE DEACETYLASES IN EPIGENETIC MODULATION OF MACROPHAGE ACTIVATION AND TRAINING

巨噬细胞是关键的免疫细胞，存在于所有组织中，协调免疫反应。这些细胞需要对不断变化的微环境具有弹性，以适当地应对各种挑战。特别是，当地微生物和细胞因子对巨噬细胞的适应(或训练)对维持免疫稳态至关重要。到目前为止，巨噬细胞是如何被各种微生物和细胞因子培养的，在很大程度上还不清楚。本研究将以活细菌(L.rhamnosus)、细菌成分(炭疽致死毒素G-CSF)为模型系统，研究巨噬细胞适应的机制。我们研究计划的总体目标是了解巨噬细胞感知、反应和适应细菌微生物和细胞因子的机制。在这一目标下，我们将着重于以下研究目标：目的1.研究组蛋白脱乙酰酶(HDAC)8在巨噬细胞培养中的作用及其表观遗传学机制。表观遗传学是一种细胞机制，它在不改变基因组序列的情况下调节基因表达，以响应环境提示。在各种表观遗传机制中，我们发现HDAC8在一种被称为炭疽致死毒素的细菌毒素训练巨噬细胞的过程中起着关键作用。然而，HDAC8及其下游通路参与巨噬细胞培养的调控机制仍有待研究。本研究将以LeTx、鼠李糖和G-CSF为模型系统，研究HDAC8在巨噬细胞培养中的作用及其机制。这将为HDAC8的生物学及其在巨噬细胞培养中的作用机制提供新的信息。目的2.通过肠道共生体检测HDACs在巨噬细胞培养中的作用。培养巨噬细胞以适当的方式做出反应对于肠道的免疫动态平衡是必不可少的，因为巨噬细胞必须耐受大量的微生物成分，同时对入侵的病原体保持警惕。除HDAC8外，其他HDACs可能还参与训练巨噬细胞表达不同的细胞因子。本研究的目的是研究除HDAC8外的其他HDACs在以鼠李糖和G-CSF为模型系统培养的巨噬细胞中调节不同细胞因子表达的作用。此外，这一目标将提纯/鉴定训练巨噬细胞的鼠李糖分泌因子(S)。总而言之，这一目标将为HDAC在肠道微生物和细胞因子训练巨噬细胞中的作用提供新的信息。总体而言，我们的研究将提供关于训练巨噬细胞对微生物成分做出适当反应并维持免疫平衡的表观遗传机制的基本信息。

Macrophages are key immune cells which reside in all tissues and orchestrate immune responses. These cells need to be resilient to changing micro-environments to appropriately respond to various challenges. Particularly, adaptation (or training) of macrophages by local microbes and cytokines are crucial for maintaining immunological homeostasis. To date, how macrophages are trained by various microbes and cytokines remains largely unknown. This research will study the mechanisms of macrophage adaptation mediated by live bacteria (L. rhamnosus), bacterial components (anthrax lethal toxin G-CSF) as model systems. The overall goal of our research program is to understand the mechanisms by which macrophages sense, respond and adapt to bacterial microbes and cytokines. Under this goal, we will focus on the following research Aims:Aim 1. Examining the role and epigenetic mechanism of the histone deacetylase (HDAC) 8 in macrophage training. Epigenetics is a cellular mechanism that regulates gene expression without altering genomic sequences in response to environmental cues. Among various epigenetic mechanisms, we found that HDAC8 plays a key role in training macrophages by a bacterial toxin, known as anthrax lethal toxin. However, the regulatory mechanisms of HDAC8 and its down-stream pathway involved in macrophage training remain to be addressed. This Aim will study the role and mechanism of HDAC8 in macrophage training by LeTx, L. rhamnosus and G-CSF in the expression of the inflammatory cytokine interleukin-1 as model systems. This Aim will provide new information on the biology of HDAC8 and its mechanism in training macrophages.Aim 2. Examining the role of HDACs in macrophage training by intestinal commensals. Training macrophages to respond in an appropriate manner is imperative for immune homeostasis of the intestine, since macrophages must tolerate a heavy load of microbial components, and yet remain vigilant to invading pathogens. In addition to HDAC8, other HDACs are likely involved in training macrophages in the expression of different cytokines. This Aim will examine the role of other HDACs than HDAC8 in regulating expression of different cytokines in macrophages trained by L. rhamnosus and G-CSF as model systems. In addition, this Aim will purify/identify the L. rhamnosus-secreted factor(s) that trains macrophages. Collectively, this Aim will provide new information on the role of HDACs in training macrophages by intestinal microbes and cytokines.Overall, our research will provide fundamental information on the epigenetic mechanisms that train macrophages to appropriately respond to microbial components and maintain immunological homeostasis.