揭示由不同免疫介导疾病患者中晚期糖基化终产物（AGEs）修饰的人血清白蛋白（AGE-HSA）引发的炎症衰老的分子基础。

Unveiling the molecular basis of inflamm-aging induced by advanced glycation end products (AGEs)-modified human serum albumin (AGE-HSA) in patients with different immune-mediated diseases.

机构信息

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan.

出版信息

Clin Immunol. 2023 Jul;252:109655. doi: 10.1016/j.clim.2023.109655. Epub 2023 May 29.

DOI:10.1016/j.clim.2023.109655

PMID:37257547

Abstract

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO incubator for 0-180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 μg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated β-galactosidase (SA-βgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-βgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-βgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-β, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

摘要

血清中晚期糖基化终产物（AGEs）在糖尿病（DM）、衰老相关疾病和免疫介导性疾病患者中普遍存在。这些疾病以血管病变、免疫功能障碍和低度炎症为特征，类似于炎症性衰老。然而，AGEs 相关炎症性衰老的分子基础仍有待阐明。在这项研究中，我们将人血清白蛋白（HSA）和葡萄糖在 37°C 和 5%CO 培养箱中孵育 0-180 天，以生成 AGE-HSA。我们发现混合物在孵育过程中逐渐从透明变为棕色，分子量逐渐增加。pH 值也逐渐从 7.2 降低至 5.4，与离子电荷或[Ca]浓度无关，但依赖于碱性氨基酸赖氨酸和精氨酸的逐渐糖化。功能上，40μg/mL 的 AGE-HSA 通过抑制 p-STAT3、p-STAT4 和 p-STAT6 降低人 Jurkat T 细胞系的 IL-2 产生，同时增加衰老相关的β-半乳糖苷酶（SA-βgal）表达，但与 Th1/Th2/Treg 亚群的变化无关。相比之下，AGE-HSA 增强了人巨噬细胞样 THP-1 细胞中 CC 基序趋化因子配体 5（CCL-5）、IL-8、巨噬细胞迁移抑制因子（MIF）和白细胞介素 1 受体拮抗剂（IL-1Ra）的表达，但抑制了 SA-βgal 的表达。有趣的是，AGE-HSA 阻断了 HSA 诱导的人冠状动脉内皮细胞（HCAEC）中可溶性细胞间黏附分子 1（sICAM-1）、sE-选择素和内皮素的释放，并增强了 SA-βgal 的表达。在体外研究中，个体炎症相关细胞因子（如 IL-2、IL-6、IL-17、TGF-β 或 TNF-α）加速和增加 HSA 糖化，反映了免疫介导性疾病患者血清中 AGE 水平升高。总之，AGE-HSA 可在这些患者中发挥免疫抑制、炎症和血管病变作用，类似于炎症性衰老。