The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases

• 成果类型: Article
• 署名作者: Kim, Hyelim; Park, Hee Ho; Kim, Hong Nam; Seo, Donghyuk; Hong, Kyung Soo; Jang, Jong Geol; Seo, Eun U.; Kim, In- Young; Jeon, So- Young; Son, Boram; Cho, Seong-Woo; Kim, Wantae; Ahn, June Hong; Lee, Wonhwa
• 署名单位: Korea Institute of Science & Technology (KIST); Yonsei University; Hanyang University; Hanyang University; Yonsei University; Yonsei University; Sungkyunkwan University (SKKU); Yeungnam University; Yeungnam University; University of Seoul
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15374
• DOI: 10.1073/pnas.2319322121
• 发表日期: 2024-06-25
• 关键词: cell; receptor; sepsis; hmgb1

摘要

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.