Abstract
IntroductionHigh mobility group box-1 (HMGB1), a typical damage-associated molecular pattern (DAMP) protein, is associated with inflammatory conditions and tissue damage. Our recent study found that circulating HMGB1 levels could reflect the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate whether HMGB1 participated in ANCA-induced neutrophil activation, which is one of the most important pathogenic aspects in the development of AAV.MethodsThe various effects of HMGB1 in ANCA-induced neutrophil activation were measured. Antagonists for relevant receptors and signaling molecules were employed.ResultsANCA antigens translocation on neutrophils primed with HMGB1 was significantly higher than non-primed neutrophils. The levels of respiratory burst and degranulation increased significantly in HMGB1-primed neutrophils activated with ANCA-positive IgG, as compared with non-primed neutrophils. Furthermore, blocking Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), rather than TLR2, resulted in a significant decrease in HMGB1-induced ANCA antigens translocation, respiratory burst and degranulation. Similar effects were also found when blocking MyD88 and NF-κB.ConclusionsHMGB1 could prime neutrophils by increasing ANCA antigens translocation, and the primed neutrophils could be further induced by ANCA, resulting in the respiratory burst and degranulation. This process is TLR4- and RAGE-dependent through the MyD88/NF-κB pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0587-4) contains supplementary material, which is available to authorized users.
Highlights
High mobility group box-1 (HMGB1), a typical damage-associated molecular pattern (DAMP) protein, is associated with inflammatory conditions and tissue damage
The effect of HMGB1 on neutrophils was dose-dependent First, neutrophils were incubated with various concentrations of HMGB1 (1, 2, 5, 10, 100 and 1000 ng/ml), and mPR3 expression was determined by flow cytometry
We showed that parallel experiments blocking Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) resulted in a significant decrease in HMGB1-induced translocation of mPR3. mPR3 expression decreased from 236.15 ± 24.79 in HMGB1-primed neutrophils to 159.54 ± 22.96 by preincubating with anti-TLR4 antibody (P
Summary
High mobility group box-1 (HMGB1), a typical damage-associated molecular pattern (DAMP) protein, is associated with inflammatory conditions and tissue damage. Our recent study found that circulating HMGB1 levels could reflect the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate whether HMGB1 participated in ANCA-induced neutrophil activation, which is one of the most important pathogenic aspects in the development of AAV. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) consists of granulomatosis with polyangiitis (GPA, previously named Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiits (EGPA) [1]. ANCA-induced neutrophil activation is increasingly being recognized to play an important role in the pathogenesis of AAV. ANCAs could further activate primed neutrophils to undergo a respiratory burst and degranulation, which plays a direct pathogenic role in the development of vasculitis [2,3,4,5,6]. It was demonstrated that in animal studies that ANCA and neutrophils were necessary for the pathogenesis of AAV [7,8]
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