AIMS/HYPOTHESIS High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a 'danger signal' (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. METHODS In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULTS Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. CONCLUSIONS/INTERPRETATION The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes.

中文翻译：

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细胞外HMGB1通过破坏调节性T细胞稳定性而加剧自身免疫进展和1型糖尿病复发。

目的/假说高迁移率第1盒（HMGB1）是一种进化上保守的染色体蛋白，被重新发现是一种“危险信号”（alarmin），一旦在细胞外释放，就会提醒免疫系统。因此，已经认识到其有助于自身免疫性糖尿病的发病机理，但是其对1型糖尿病的起始和进展以及相关分子机制的确切影响尚待充分表征。方法在本报告中，我们以NOD小鼠为模型，研究了阻断HMGB1对1型糖尿病的预防，治疗和逆转的影响。为了研究涉及的机制，我们广泛研究了调节性T细胞（Tregs）的特征及其在HMGB1刺激下的相关信号通路。此外，我们调查了我们的数据与人类自身免疫性糖尿病的相关性。结果中和HMGB1不仅延缓了糖尿病的发作，而且特别相关的是，在20只新发病的糖尿病NOD小鼠中，有13只糖尿病逆转了糖尿病。一致地，在糖尿病NOD小鼠中，HMGB1的阻断可防止胰岛同种异体移植物免受自身免疫攻击。使用携带Foxp3谱系报道基因构建体的转基因报道基因小鼠，我们发现HMGB1的给药会损害Treg的稳定性和功能。机理研究表明，HMGB1激活AGE（RAGE）受体和toll样受体（TLR）4，以增强雷帕霉素（mTOR）信号转导的磷脂酰肌醇3-激酶（PI3K）-Akt机制靶标，从而损害Treg的稳定性和功能性。确实，患有1型糖尿病的人类受试者中HMGB1的高循环水平会导致Treg不稳定，提示在临床环境中阻断HMGB1可能是针对1型糖尿病的有效疗法。结论/解释本数据支持HMGB1可能是一种可行的治疗靶标，可以预防1型糖尿病患者自身免疫的发生，发展和复发。