HMGB1‐induced asthmatic airway inflammation through GRP75‐mediated enhancement of ER‐mitochondrial Ca2+ transfer and ROS increased

Abstract Imbalanced T‐helper (TH)1/Th2 response contributes significantly to asthma pathogenesis. Our study indicated that HMGB1 play an important role in the release of Th2‐associated cytokines of asthma. However, the specific mechanism about HMGB1‐induced imbalanced TH1/Th2 response is not known. In vivo, an OVA‐induced asthma mouse model was set up and mice treated with anti‐HMGB1 IgG. The mice treated with the anti‐HMGB1 IgG ameliorated airway hyper‐reactivity, disruption of Th1/Th2 balance and the upregulation of GRP75 induced by OVA. In vitro, the exposure of normal human bronchial epithelial cells to HMGB1 resulted in the upregulation of GRP75, proinflammatory cytokine production, enhanced ER‐Mitochondrial Ca 2+ transfer, and enhancement of reactive oxygen species (ROS). While HMGB1‐induced these changes were attenuated by GRP75 siRNA treatment. Sequentially, pretreatment with 2‐APB, SKF960365 (SKF) and Ru360 which inhibit ER‐Mitochondrial Ca 2+ transfer significantly lowered HMGB1‐induced the generation of ROS and the release of Th2 cytokines in 16HBE cells. Meanwhile, N‐acetylcysteine (NAC) significantly attenuated the HMGB1‐mediated pro‐inflammatory cytokines release. Therefore, these results indicate that GRP75‐mediated ER‐Mitochondrial Ca 2+ transfer may be an important contributor in imbalanced of Th1/Th2 balance of asthma. Moreover, HMGB1 specifically induces the release of Th2 cytokines through GRP75‐mediated enhancement of ER‐Mitochondrial Ca 2+ transfer and ROS increased.