{Reference Type}: Journal Article
{Title}: The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.
{Author}: Kim H;Park HH;Kim HN;Seo D;Hong KS;Jang JG;Seo EU;Kim IY;Jeon SY;Son B;Cho SW;Kim W;Ahn JH;Lee W;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 121
{Issue}: 26
{Year}: 2024 Jun 25
{Factor}: 12.779
{DOI}: 10.1073/pnas.2319322121
{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.