The expression and function of RAGE and HMGB1 in airway structural cells in asthma

Asthma is characterised by airway hyperresponsiveness, airflow obstruction, chronic inflammation and airway remodelling, with an increase in airway smooth muscle (ASM) mass and contractility. ASM also releases mediators that support inflammation and remodelling. High-mobility group box 1 (HMGB1) is a nuclear protein that is released by damaged/stressed cells and activated immune cells. HMGB1 signals through pattern recognition receptors (PRRs) including the receptor for advanced glycosylation end products (RAGE) to promote inflammation and tissue repair. HMGB1 binding and function are governed by its redox state. Evidence suggests HMGB1 elevation in asthma; however, the redox state of airway HMGB1 is unknown. Moreover, the expression and role of RAGE in regulating airway mesenchymal cells are unknown. We aimed to investigate HMGB1 and RAGE expression in bronchial tissue; the redox form of sputum HMGB1; the expression and role of HMGB1 and RAGE in airway structural cells. HMGB1 was 3.5-fold higher in sputa of moderate-to-severe asthmatics (n=34), and the reduced form was shown to be increased in this group (n=16) for the first time. Reduced HMGB1 was chemotactic for peripheral blood leukocytes, and sputum HMGB1 correlated with sputum total cell counts. HMGB1, but not RAGE, expression was ~3-fold higher ex vivo in ASM of severe asthmatics (n=16). ASM and human bronchial epithelial cells (HBECs) expressed both HMGB1 and cell-surface RAGE in vitro. HMGB1 expression was upregulated in ASM cells stimulated with inflammatory cytokines. HMGB1 stimulation caused increased reactive oxygen species production in ASM cells from non-asthmatics, but not in asthmatics; ASM contraction and inhibition of ASM cell migration and HBEC wound healing. These results suggest that HMGB1 promotes inflammatory cell recruitment, impairs epithelial and ASM repair, and promotes ASM contraction in asthma. Further work is required to determine whether antagonising HMGB1 or its receptors would be a viable therapeutic approach for the treatment of asthma.