HMGB1 Binding to the RAGE Receptor Contributes to the Pathogenesis of Asthma

Objective: High-mobility group box 1 protein (HMGB1) serves as an inflammatory mediator and has been implicated in the pathogenesis of asthma. Extracellular HMGB1 transduces cellular signals through the plasma membrane receptor for advanced glycation end products (RAGE). The HMGB1/RAGE axis has proven to be a pivotal factor in the progression of tumor growth and inflammation. In this study, we sought to determine whether HMGB1 signaling through RAGE occurs in asthma. Methods: C57BL/6 mice were randomly divided into 4 groups, asthma mice; nonasthma control mice; glycyrrhizic acid ammonium salt from glycyrrhiza root (GL) therapy mice; and high-affinity RAGE-specific inhibitor (FPS-ZM1) therapy mice. Asthmatic mice were sensitized and challenged with ovalbumin (OVA), and control mice were treated with saline. These 2 groups were divided into 4 subgroups, which were sacrificed at days 21, 28, 35, and 42. GL and FPS-ZM1 therapy mice were first sensitized with OVA at days 0 and 7 and then injected intraperitoneally with GL (20mg/kg) or FPS-ZM1 (5mg/kg) 30min before each challenge. The gene expressions were measured by RT-PCR. Hematoxylin-eosin staining was used to observe mouse lung structural changes. Immunofluorescence immunohistochemistry was used to detect HMGB1 and RAGE proteins in lung tissue. The expressions of HMGB1, toll-like receptor 2 (TLR2), TLR4, and RAGE were significantly increased in asthma mice (P<0.05). In addition, HMGB1 and RAGE displayed similar trends over time; both reached a peak at day 28 in asthma mice and then gradually declined. Infiltration of inflammatory cells into lung tissue, L-4, and IL-13 expression in asthma mice was suppressed after treatment with either the HMGB1 or the RAGE inhibitor. The effect of FPS-ZM1 was weaker than that of the GL therapy. Conclusion: In conclusion, a part of the HMGB1 contribution to the pathogenesis of asthma was mediated through binding to RAGE.