PDF(Pubmed)
Abstract：
Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.
摘要：
胸腺细胞选择相关的高迁移率组框（TOX）是一种转录因子，在慢性抗原刺激期间对T细胞衰竭至关重要，但它在炎症中的作用知之甚少。这里,我们报道,在严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)感染时,TOX通过与晚期糖基化终产物(RAGE)的细胞表面受体结合,在细胞外介导剧烈炎症.在各种疾病中，包括COVID-19，TOX释放与疾病严重程度高度相关，导致肺纤维化增殖性急性呼吸窘迫综合征（ARDS）。重组TOX诱导的血管破裂，类似于经历细胞因子风暴的患者的临床特征，进一步加重呼吸功能损害。相比之下,中和抗体对TOX功能的破坏和RAGE的遗传去除减少了TOX介导的有害作用。总之,我们的结果提示我们对TOX作为炎症介质的功能有了深入的了解,并提出TOX-RAGE轴作为治疗重症肺部感染患者和减轻肺纤维化增殖性ARDS的潜在靶点.
