HMGB1 recruits natural killer cells by CXCL12/CXCR4 axis contributing to persistent airway inflammation and airway hyperresponsiveness during the late stage of respiratory syncytial virus infection

Abstract We previously showed that both high-mobility group box-1 (HMGB1) and natural killer (NK) cells contribute to respiratory syncytial virus (RSV)-induced persistent airway inflammation and airway hyperresponsiveness (AHR). Meanwhile, Chemokine (C-X-C motif) ligand 12 (CXCL12) and its specific receptor (chemokine receptor 4, CXCR4) were reported to play important roles in recruitment of immune cells. The relationships between them remains unclear. Here, we investigated whether HMGB1 recruits NK cells via the CXCL12/CXCR4 axis, thereby mediating RSV-induced persistent airway disorders. An anti-HMGB1 neutralizing antibody and inhibitor of CXCR4 (AMD3100) was administered to observe changes in the percentage of NK cells and airway disorder in nude mice. Results showed that the mRNA and protein expression levels of HMGB1 were elevated in late stage of RSV infection and persistent airway inflammation and AHR were diminished after administration of anti-HMGB1 antibodies, with an associated significant decrease in NK cells. In addition, CXCL12 and CXCR4 were reduced after HMGB1 blockade. Treatment with AMD3100 significantly suppressed the recruitment of NK cells and alleviated the airway disorders. Thus, HMGB1 recruits NK cells through the CXCL12/CXCR4 axis, leading to persistent airway inflammation and AHR in late stage of RSV infection.