a Department of Women's and Children's Health, Center for Molecular Medicine (CMM) L8:04, Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden.
b Laboratory of Biomedical Science , The Feinstein Institute for Medical Research , Manhasset , NY , USA.
Expert Opin Ther Targets. 2018 Mar;22(3):263-277. doi: 10.1080/14728222.2018.1439924. Epub 2018 Feb 15.
High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that promotes inflammation when released extracellularly after cellular activation, stress, damage or death. HMGB1 operates as one of the most intriguing molecules in inflammatory disorders via recently elucidated signal and molecular transport mechanisms. Treatments based on antagonists specifically targeting extracellular HMGB1 have generated encouraging results in a wide number of experimental models of infectious and sterile inflammation. Clinical studies are still to come. Areas covered: We here summarize recent advances regarding pathways for extracellular HMGB1 release, receptor usage, and functional consequences of post-translational modifications. The review also addresses results of preclinical HMGB1-targeted therapy studies in multiple inflammatory conditions and outlines the current status of emerging clinical HMGB1-specific antagonists. Expert opinion: Blocking excessive amounts of extracellular HMGB1, particularly the disulfide isoform, offers an attractive clinical opportunity to ameliorate systemic inflammatory diseases. Therapeutic interventions to regulate intracellular HMGB1 biology must still await a deeper understanding of intracellular HMGB1 functions. Future work is needed to create more robust assays to evaluate functional bioactivity of HMGB1 antagonists. Forthcoming clinical studies would also greatly benefit from a development of antibody-based assays to quantify HMGB1 redox isoforms, presently assessed by mass spectrometry methods.
高迁移率族蛋白 B1（HMGB1）是一种普遍存在的核蛋白，在细胞激活、应激、损伤或死亡后释放到细胞外时会促进炎症。HMGB1 通过最近阐明的信号和分子转运机制，作为炎症性疾病中最引人注目的分子之一发挥作用。基于专门针对细胞外 HMGB1 的拮抗剂的治疗方法在许多感染性和无菌性炎症的实验模型中产生了令人鼓舞的结果。临床研究仍在进行中。
我们在这里总结了关于细胞外 HMGB1 释放、受体使用以及翻译后修饰的功能后果的最新进展。该综述还讨论了多种炎症情况下的临床前 HMGB1 靶向治疗研究的结果，并概述了新兴临床 HMGB1 特异性拮抗剂的现状。
阻断过量的细胞外 HMGB1，特别是二硫键异构体，为改善全身炎症性疾病提供了一个有吸引力的临床机会。调节细胞内 HMGB1 生物学的治疗干预措施仍需等待对细胞内 HMGB1 功能的更深入了解。需要进一步的研究来创建更强大的测定法来评估 HMGB1 拮抗剂的功能生物活性。即将进行的临床研究也将从开发基于抗体的测定法来量化 HMGB1 氧化还原异构体中大大受益，目前这些测定法是通过质谱方法评估的。
