HMGB1-TLR4通路在干燥综合征唾液腺损伤中的作用及机制

Salivary gland (SG) is the most frequently involved organ in Sjogren's syndrome (SS). Local inflammatory cells infiltration of SG resulted in inadequate gland secretion is the hallmark characteristic of SS. Currently, the clinical treatment of SS is very limited. Thus, it is essential to explore the important molecule that can regulate the SG immune damage. HMGB1 released in pathological condition is a typical damage-associated molecular pattern, which can participate in many diseases. Our preliminary experiments showed that the mRNA levels of HMGB1 and its receptor TLR4 were up-regulated in SG tissues of SS patients and animal models, and the release of HMGB1 to extracellular matrix was also increased, which was negatively correlated with salivary secretion. Based on the research, we hypothesized that HMGB1-TLR4 pathway may be involved in SG immune damage and thus promote the development of SS. We will use the NOD spontaneous SS model and patient specimens, to investigate the dynamic changes of HMGB1 and TLR4 expression in salivary gland of SS, explore the role of HMGB1-TLR4 pathway in the dysfunction of salivary gland in SS, and clarify that HMGB1 may promote DC maturation and antigen presentation, and inhibit macrophage phagocytosis clearance through positive feedback to enhance immune response and thus salivary gland injury. Carrying out this issue is hopeful to provide research basis for exploring new clinical intervention strategies of SS.

唾液腺(SG)是干燥综合征(SS)最常受累器官，SG局部炎性细胞浸润导致腺体分泌功能不足是其典型特征。目前该疾病治疗方案非常有限，深入探讨可调控SG免疫损伤的关键靶分子尤为重要。病理情况下释放至胞外的HMGB1是一种典型的损伤相关分子模式，可参与多种疾病的发生发展。我们预实验发现，SS患者及动物模型的SG组织HMGB1及其受体TLR4转录水平上调，释放至胞外的HMGB1亦增加，并与唾液分泌呈负相关。由此推测，HMGB1-TLR4通路可能参与了SG免疫损伤进而促进SS发生发展。本项目拟借助NOD自发SS模型及患者标本，研究SS唾液腺局部HMGB1及TLR4的表达动态变化，探讨HMGB1-TLR4通路在SS唾液腺损伤中的作用，并阐明HMGB1可能通过正反馈促进DC成熟和抗原递呈，同时抑制巨噬细胞吞噬清除作用以增强免疫反应从而导致腺体损伤。本项目的开展有望为SS探寻新的临床干预策略提供实验依据。

唾液腺（SG）是干燥综合征（SS）最常受累器官，SG局部炎性细胞浸润导致腺体分泌功能不足是其典型特征。目前该疾病治疗方案非常有限，深入探讨可调控SG免疫损伤的关键靶分子尤为重要。病理情况下释放至胞外的HMGB1是一种典型的损伤相关分子模式，可参与多种疾病的发生发展。但它在SS腺体免疫损伤中的作用及机制尚无明确报道。本项目研究发现：1）SS患者活检唇腺组织和干燥样NOD小鼠唾液腺组织HMGB1表达上调并有胞外转位；2）SS患者活检唇腺组织和NOD小鼠唾液腺组织TLR4表达上调；3）HMGB1通过TLR4促进了巨噬细胞成熟和抗原呈递，促进了受累腺体炎症和免疫相关信号通路活化；4）甘草甜素GL（HMGB1抑制剂）治疗改善了NOD小鼠唾液腺组织分泌功能；5）还发现另一种损伤相关分子模式IL-33与poly(I:C)诱导加重SS有关；6）SS患者外周血的NK细胞亚群有助于SS的鉴别诊断。本项目的开展不仅加深人们对SS发病机制的理解和认识，而且为靶向调控HMGB1-TLR4通路以有效减轻SS组织免疫损伤提供了研究依据，为更好的改善SS患者预后提供了新的潜在靶点。