Origin and function of the endogenous danger signal HMGB1 in the inflammatory response following infectious and immunological liver injury.

炎症是大多数肝脏疾病的组成部分，并会导致器官损伤。虽然不同的细胞因子和趋化因子在肝脏炎症调节中的作用已经很好地建立，但尚不清楚这些炎症反应是如何引发的。通常认为，应激或受损细胞可以释放通过进化上保守的受体系统触发炎症的细胞组分，因此称为损伤相关分子模式。相比之下，病原体的分子成分，如脂多糖，被认为在感染的情况下触发炎症，因此被称为病原体相关的分子模式。然而，无菌性和感染性炎症之间的这种概念上的区别正在被一种概念所取代，在这种概念中，实质细胞、炎性细胞和病原体（在适用的情况下）进入动态相互作用的复杂相互作用。内源性危险信号在这些相互作用的调节中的作用是越来越多的科学兴趣的主题。广泛表达的核蛋白HMGB1由坏死细胞释放，也可由活化的炎性细胞分泌。通过与炎症细胞上的受体TLR2和TLR4相互作用，它被认为发挥促炎作用，然而，清洁的遗传消融研究已被全球Hmgb1基因敲除动物的出生后早期致死性所排除。在以前的研究中，小鼠进行条件Hmgb1消融，我们可以证明，该蛋白质可以有效地从各种组织的成年生物体，而不影响细胞的稳态或功能，但它是必不可少的启动炎症反应后无菌组织损伤。在这里，我们试图测试的假设，抑制炎症的情况下，HMGB1排除了有效的免疫宿主对感染性和免疫性肝损伤的反应。为此，我们的目标是首先确定HMGB1在细菌和病毒感染以及免疫性肝损伤小鼠模型中的主要细胞来源。接下来，我们将从肝细胞、内皮细胞或白细胞中特异性地删除该基因，并研究对上述损伤模型的免疫应答的各自影响。进一步的研究旨在确定相关的HMGB1受体以及HMGB1对参与这种反应的实质和炎症细胞群的不同作用。最后，针对HMGB1及其受体的药物干预的可能性将得到解决，以及差异乙酰化HMGB1形式和患者血清中天然存在的HMGB1自身抗体作为感染性和免疫性肝病管理中的诊断和预后工具的适用性。

Inflammation is an integral component of most liver diseases and contributes to organ damage. While the roles of distinct cytokines and chemokines in the regulation of hepatic inflammation are well established, it is unclear how these inflammatory responses are intiated. It is generally assumed that stressed or damaged cells can release cellular components that trigger inflammation through evolutionarily conserved receptor systems, and are thus termed damage associated molecular patterns. By contrast, molecular constituents of pathogens, such as lipopolysaccharide, are believed to trigger inflammation in the setting of infection, and are thus called pathogen associated molecular patterns. This conceptual distinction between sterile and infectious inflammation, however, is being replaced by a concept in which parenchymal cells, inflammatory cells and, where applicable, pathogens enter a complex interplay of dynamic reciprocal interactions. The role of endogenous danger signals in the regulation of these interactions is subject of a growing scientific interest. The ubiquitously expressed nucleoprotein HMGB1 is released by necrotic cells and can also be secreted by activated inflammatory cells. Through interactions with its receptors RAGE, TLR2 and TLR4 on inflammatory cells, it is believed to exert proinflammatory effects, however, clean genetic ablation studies have been precluded by the early postnatal lethality of global Hmgb1 knockout animals. In previous investigations on mice carrying conditional Hmgb1 ablation, we could demonstrate that the protein can be efficiently removed from various tissues of the adult organism without affecting cellular homeostasis or function, but that it is essential for the initiation of an inflammatory response following sterile tissue damage. Here, we seek to test the hypothesis that suppressed inflammation in the absence of HMGB1 precludes an efficient immunological host response to infectious and immunological liver damage. To this end, we aim to first identify the main cellular source of HMGB1 in mouse models of bacterial and viral infection as well as immunological liver damage. Next, we will delete the gene specifically from hepatocytes, endothelial cells or leukocytes and study the respective effects on the immunological response to the aforementioned injury models. Further investigations aim to identify relevant HMGB1 receptors as well as differential effects of HMGB1 on parenchymal and inflammatory cell populations involved in this response. Finally, the possibility of pharmacological interventions aimed at HMGB1 and its receptors will be addressed as well as the applicability of differentially acetylated HMGB1 forms and naturally occuring HMGB1 autoantibodies in patient sera as diagnostic and prognostic tools in the management of infectious and immunological liver diseases.