title: High mobility group box 1 contributes to anti-neutrophil cytoplasmic antibody-induced neutrophils activation through receptor for advanced glycation end products (RAGE) and Toll-like receptor 4.
abstract: BACKGROUND
  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.
  
  
  METHODS
  The various effects of HMGB1 in ANCA-induced neutrophil activation were measured. Antagonists for relevant receptors and signaling molecules were employed.
  
  
  RESULTS
  ANCA 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.
  
  
  CONCLUSIONS
  HMGB1 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.
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. wangchen8784@163.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. hopewanghuan@sina.com.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. cdy@outlook.com.
authors.forename: Dong-Yuan
authors.initials: DY
authors.lastname: Chang
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. jian_hao8865@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. mhzhao@bjmu.edu.cn.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, 8, Xishiku Street, Beijing, 100034, China. chenmin74@sina.com.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
mesh_terms: D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000096:biosynthesis / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D024243:HMGB1 Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4