High mobility group box chromosomal protein 1 (HMGB1) is a critical pro-inflammatory cytokine involved in diverse inflammatory diseases and has important immunomodulatory effects on allergic asthma. Our recent studies demonstrate that HMGB1) ˆReloadFigure=Yes1 expression increases in the lung tissue and associates with interleukin-17+ (IL-17) helper T cell (Th17) responses in a murine model of neutrophilic asthma. In this study, to examine the immunomodulatory mechanisms of HMGB1, we evaluated the effects of recombinant HMGB1 A box (an antagonist of HMGB1) administration on allergic airway inflammation and lung antigen-presenting cell (APC) function in a murine model of neutrophilic asthma. In OVA-challenged mice, rHMGB1 A box attenuated HMGB1 expression, airway neutrophilic inflammation and hyper-responsiveness. In addition, the administration of rHMGB1 A box decreased the number of Th17 cells and IL-23+ CD11c+ APCs in lung cells. In vivo, rHMGB1 A box revealed an inhibitory effect of rHMGB1-activated dendritic cells (DCs) to produce IL-23 and induce a Th17 response. Finally, we showed that adoptive transfer of rHMGB1-activated DCs was sufficient to restore the characteristics of neutrophilic asthma in a DCs-driven model of asthma, whereas the transfer of rHMGB1 A box plus rHMGB1-activated DCs significantly reduced these inflammation phenotypes. These data demonstrate that rHMGB1 A box may have therapeutic effects on controlling Th17 polarization and airway inflammation in neutrophilic asthma by blocking the HMGB1 pathway on DCs.