%0 Journal Article
%T The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.
%A Kim H
%A Park HH
%A Kim HN
%A Seo D
%A Hong KS
%A Jang JG
%A Seo EU
%A Kim IY
%A Jeon SY
%A Son B
%A Cho SW
%A Kim W
%A Ahn JH
%A Lee W
%J Proc Natl Acad Sci U S A
%V 121
%N 26
%D 2024 Jun 25
%M 38900789
%F 12.779
%R 10.1073/pnas.2319322121
%X 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.