title: Anti-HMGB1 neutralizing antibody ameliorates neutrophilic airway inflammation by suppressing dendritic cell-mediated Th17 polarization.
abstract: We demonstrate that high mobility group box 1 protein (HMGB1) directs Th17 skewing by regulating dendritic cell (DC) function. First, our in vitro studies reveal that recombinant HMGB1 (rHMGB1) activates myeloid DCs to produce IL-23 in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretion in vivo by using a murine model of neutrophilic asthma induced by ovalbumin (OVA) plus lipopolysaccharide (LPS). Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C(+) APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: Fang
authors: 0000-0002-7464-3434
authors: F
authors: Zhang
authors: Department of Medical Genetics, Third Military Medical University, Chongqing 430038, China.
authors: Gang
authors: G
authors: Huang
authors: Department of Administration, 105 Hospital, Hefei 230031, China.
authors: Bo
authors: B
authors: Hu
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: Li-Ping
authors: LP
authors: Fang
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: E-Hong
authors: EH
authors: Cao
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: Xiao-Feng
authors: XF
authors: Xin
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: Yong
authors: Y
authors: Song
authors: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors: Yi
authors: Y
authors: Shi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001249:Asthma / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000276:immunology*; D007249:Inflammation; D053759:Interleukin-23 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008168:Lung / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D010047:Ovalbumin / Q000737:chemistry; D010641:Phenotype; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D039521:CD11c Antigen; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D053759:Interleukin-23; D008070:Lipopolysaccharides; D010047:Ovalbumin