巨噬细胞能量代谢与肝脏损伤后修复的关联及其机制研究

Macrophages represent an innate immune cell type that can execute a variety of functions. Besides it role in mediating an immune response, macrophages are also key to tissue repair responses. Currently, mechanisms regulating these cells’ pro-repair functions are not well known. We hypothesize that energy metabolism is linked to these cells’ acquisition of a repair phenotype. We plan to focus on the acute liver injury model. The metabolic changes in macrophages from the injured livers would provide angles to further tease out new mechanisms regulating the repair macrophages. Based on preliminary results, we will investigate the sequential activation of glycolysis and later, the fatty acid oxidation in macrophages after their arrival at the injured liver. Both genetic and pharmacological approaches will be utilized. We will also rely on both educated guesses and un-biased tools, to seek the connections between metabolism and the repair phenotypes of the macrophages. We will further extend our basic research into looking for agents targeting the related immunometabolic pathways in the hope to promote tissue repair after liver injuries. Lastly, our collaborators from the clinics will seek to determine several immunometabolic paramaters using the blood monocytes from patients undergone liver surgeries. Potential association of such parameters with the prognosis would be investigated. Our work shall further uncover deep connections between metabolism and the immune system. Moreover, our efforts shall encourage the translation of basic research in the field of immunometabolism to clinical applications.

巨噬细胞是一类具有非常广泛功能的天然免疫细胞，在介导免疫应答外，也可以显著促进组织损伤修复。目前，调控这些细胞修复功能的机制还不清楚。我们假设能量代谢与修复性巨噬细胞的分化、功能相关。我们计划以小鼠急性肝脏损伤为模型，以损伤组织中巨噬细胞的能量代谢改变为切入点，籍此深入探讨调控修复性巨噬细胞功能的新机制。基于前期结果，我们将聚焦在修复性巨噬细胞分化过程中依次出现的糖酵解及随后的脂肪酸氧化的激活上。我们将利用遗传学与药理学干预手段，结合逻辑推理与非偏向性的探索，努力寻找代谢与修复性巨噬细胞分化、功能的偶联。基于这些基础研究，我们也将尝试通过靶向免疫代谢，促进肝脏损伤后恢复。最后，课题组的临床团队将尝试测量肝脏手术病人血液单核细胞的相关免疫代谢指标，并寻找这些指标可能和病人预后间的相关性。我们的研究将进一步深入挖掘能量代谢与免疫系统的复杂联系，并有力推动巨噬细胞免疫代谢的转化医学研究。

巨噬细胞是一类具有非常广泛功能的天然免疫细胞，在介导免疫应答外，也可以显著促进组织损伤修复。目前，调控这些细胞修复功能的机制还不清楚。我们首先基于小鼠急性肝脏损伤修复模型，探讨了不同类型巨噬细胞与肝损伤修复的相关性，揭示了特定类型巨噬细胞数量行为与损伤修复的不同进程的相关性。基于能量代谢影响巨噬细胞功能的假设，我们聚焦在巨噬细胞糖酵解通路。我们建立了糖酵解调控酶Pfkfb3的条件性敲除工具，开展了巨噬细胞特异性敲除。出乎意料的是，尽管Pfkfb3敲除对巨噬细胞吞噬效应及炎性通路产生了一定影响，肝脏损伤修复的情况并未显著改变，提示在该条件下体内巨噬细胞中Pfkfb3可能存在冗余性或是某种补偿机制。为了更好地研究体内与组织修复相关的M2型巨噬细胞，我们另外建立了可以用于标记这些细胞的Arg1-YFP敲入小鼠品系，该小鼠品系并也可用于条件性敲除Arg1。此外，我们选择长期polyIC（IFN-I诱导剂）治疗小鼠肿瘤为另外的模型，研究了该刺激对肿瘤相关巨噬细胞的影响。该研究首次发现肿瘤相关细胞中IFN-I至精氨酸酶作用轴，起促进肿瘤的反作用。对该轴的进一步机制分析建立了IFN-I作用于单核细胞后诱导IL-4的级联效应，随后导致巨噬细胞M2型极化，产生促肿瘤（修复）的功能。整体来说，本项目的开展对进一步深入挖掘病原、损伤作用下免疫细胞代谢、行为改变的复杂调控建立了基础，也为相关疾病的新型干预提供了新型靶点及方向。