HDAC6调控巨噬细胞和中性粒细胞向炎症部位浸润的分子机理研究

Macrophages and neutrophils are the major effector cells which infiltrate into the infected sites to clear the pathogens and necrotic cells and activate the adaptive immunity during inflammation. Aberrant infiltration of immune cells is usually associated with the development and progression of many diseases. However, the molecular mechanism underlying the regulation of immune cell infiltration remains to be elucidated yet. The immune cells that transendothelial infiltrate into the inflammatory loci must undergo the disassembly and reassembly of cytoskeleton. Interestingly, our previous studies identified histone deacetylase 6 (HDAC6) as a key player that regulates the dynamics of cytoskeleton. In this study, by using the inflammatory model and available hdac6 knockout mice, we will focus our study on HDAC6-mediated macrophage and neutrophil infiltration. To this end, the role of HDAC6 in regulation of chemotaxis of macrophages and neutrophils would be examined from multiple perspectives, including molecular and cellular levels, as well as animal models. Furthermore, the effect of HDAC6 on re-organization of microtubule and microfilament cytoskeleton at different regions of the migrating cell, including the leading edge and rear, and the molecular mechanism by which HDAC6 exerts its effect will be analyzed. Collectively, these work will provide novel insights for the better understanding of innate immunity, and shed lights on the therapeutic strategies for the treatment of immune disorders.

巨噬细胞和中性粒细胞是炎症反应中的主要效应细胞，炎症反应时它们在炎症部位的浸润有助于机体吞噬并清除外源病原微生物和坏死细胞，并激活适应性免疫。这些免疫细胞的趋化运动的异常通常与许多疾病的发生发展密切相关，但是调控这些细胞浸润的分子机理仍不很清楚。免疫细胞跨过血管内皮浸润到炎症部位必须经历细胞骨架的解聚和重组装，我们的前期研究鉴定了组蛋白去乙酰化酶HDAC6是一个重要的细胞骨架动态性调节蛋白。在本项研究中，我们将利用实验室已有的hdac6基因敲除小鼠和小鼠炎症模型，从分子、细胞和动物模型等多个层面多个视角研究HDAC6对巨噬细胞和中性粒细胞向炎症部位浸润的影响；探讨炎症反应中HDAC6如何精确地调控趋化运动的细胞前端及尾部等不同区域的微管骨架和微丝骨架动态性重塑过程，并通过比较蛋白组学、免疫荧光染色、免疫共沉淀等手段解析其中的分子机制，为深入理解固有免疫及免疫性疾病的治疗提供新的思路。

细胞运动对生物体个体发育、免疫炎症反应、损伤修复以及肿瘤转移等过程十分重要，细胞运动的异常与多种重大人类疾病密切相关，但是调控细胞运动尤其是免疫细胞趋化运动的分子机理仍不清楚。在本项目中，我们聚焦细胞骨架动态性调控这一关键的趋化运动的调控因子，开展了炎症反应中HDAC6对巨噬细胞和中性粒细胞浸润的研究工作，揭示了HDAC6调控微丝骨架和微管骨架重塑的分子机制； 我们前期研究发现HDAC6与一些重要的微管结合蛋白协同调节多种细胞活动，因此，我们探究了微管正端示踪蛋白EB1和微管去泛素化酶CYLD是否也参与HDAC6调节的细胞骨架动态性，我们的结果表明一些翻译后修饰在细胞骨架动态性调控和细胞运动及细胞分裂中也发挥着重要的作用。这些研究结果加深了对细胞运动的调控机理认识，为细胞运动相关疾病的治疗提供了重要理论依据和防治靶点。