The role of high‐mobility group box‐1 (HMGB1) in the pathogenesis of asthma

Abstract

Summary Background High‐mobility group box 1 protein (HMGB1) belonging to endogenous danger signals prolongs eosinophil survival and acts as a chemoattractant. Objective The authors evaluated the role of HMGB1 in the pathogenesis of asthma characterized by eosinophilic airway inflammation. Methods Firstly, HMGB1 expressions in induced sputum obtained from human asthmatics were determined. This was followed by an evaluation of the role of HMGB1 in a murine model of asthma using anti‐HMGB1 antibodies. Then the effect of HMGB1 on the receptor of advanced glycation end products (RAGE) expressions on CD11b‐CD11c+ cells isolated from a murine model of asthma were measured to elucidate the mechanisms involved. Results Sputum HMGB1 expressions were markedly higher in asthmatics than in normal controls, and were positively correlated with sputum eosinophilia and sputum TNF‐α, IL‐5 and IL‐13 expressions. In a murine model of asthma, HMGB1 expressions in lung tissue and HMGB1 levels in bronchoalveolar lavage fluid were significantly elevated and eosinophilic airway inflammation, non‐specific airway hyperresponsiveness, and pathological changes were attenuated by blocking HMGB1 activity. Furthermore, we found that enhanced RAGE expressions on CD11b‐CD11c+ also significantly decreased when HMGB1 activity was blocked. Conclusion and Clinical Relevance Our findings suggest that HMGB1 plays a key role in the pathogenesis of clinical and experimental asthma characterized by eosinophilic airway inflammation.

HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

“…6,21 Consistent with the findings by Shim et al, 6 administration of an anti-HMGB1 antibody resulted in decreased lung inflammation overall, resulting in reduced numbers of inflammatory cells and decreased cytokine levels. Moreover, anti-HMGB1 administration also led to a marked decrease in the number of neutrophils in the BALF.…”

“…injection on days 0, 7, and 14 with 20 mg (grade V; Sigma-Aldrich; St. Louis, MO) plus 0.5 mg aluminum hydroxide (Thermo Scientific) and then challenged from day 21 with OVA (40 mg per mouse) i.n. three times a week for 6 weeks. An anti-HMGB1 antibody (Abcam, Cambridge; MA; 50 mg/mg body weight) or an (Abcam, Cambridge; MA) was injected i.p.…”

“…HMGB1 has been shown to increase the cytokine response induced by other cytokines such as IL-1b through the formation of complexes, 13 and elevated levels of HMGB1/IL-1b complex have been found in serum from patients with asthma. 4,6 Therefore, we investigated whether the HMGB1/IL-1b complex affected the synthesis and secretion of cytokines. The cell types listed above were incubated with varying concentrations of HMGB1, IL-1b or HMGB1/IL-1b complexes.…”

“…4 We also demonstrated that HMGB1 levels are increased in the lungs as well as the bronchial alveolar lavage fluid (BALF) of ovalbumin (OVA)-induced acute asthmatic mice. 5 Shim et al 6 showed that HMGB1 plays a central role in eosinophilic airway inflammation in asthma. More interestingly, HMGB1 has been shown to play a pivotal role in pulmonary fibrosis, partly through reduction of fibroblast proliferation and downregulation of interleukin (IL)-1b levels.…”

Activation of human basophils by combined toll‐like receptor‐ and FcεRI‐triggering can promote Th2 skewing of naive T helper cells

“…Although parasites can induce specific IgE and activate TLRs through pathogen-associated molecular patterns, chronic allergic inflammation may lead to activation of TLR by damage-associated molecular patterns [30,31]. In addition, certain viral and bacterial infections have been associated with asthma exacerbations [32,33], and the presence of endotoxin (TLR-4 ligand) was demonstrated in house dust, and was related to severity of allergic reactions against house dust mite [21], Our data indicate that activation of basophils may contribute to these processes by enhanced cytokine production when both specific IgE and TLR ligands are present.…”