TY - JOUR
T1 - Anti-HMGB1 neutralizing antibody attenuates periodontal inflammation and bone resorption in a murine periodontitis model
AU - Yoshihara-Hirata, Chiaki
AU - Yamashiro, Keisuke
AU - Yamamoto, Tadashi
AU - Aoyagi, Hiroaki
AU - Ideguchi, Hidetaka
AU - Kawamura, Mari
AU - Suzuki, Risa
AU - Ono, Mitsuaki
AU - Wake, Hidenori
AU - Nishibori, Masahiro
AU - Takashiba, Shogo
N1 - Funding Information:
We thank all staff in the Okayama Medical Innovation Center and Public Laboratory at the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences for supporting the study on molecular imaging. We also thank the Department of Oral Rehabilitation and Regenerative Medicine at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences for supporting the study on non-computed tomography scanning. This work was supported by research funds from a JSPS KAKENHI Grant-in-Aid for Young Scientists (B) (JP 24792327), the Kobayashi Magobei Memorial Medical Foundation, and the Ryobi-Teien Foundation, by a Grant-in-Aid for the COE projects by MEXT, Japan, entitled "Center of excellence for molecular and gene targeting therapies with micro-dose molecular imaging modalities, " and by a Translational Research Network Program (no. H27 seeds B-8-1) from Japan AMED. We declare no potential conflicts of interest with respect to the authorship and/or publication of this article
PY - 2018/5/1
Y1 - 2018/5/1
N2 - High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocytemacrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro. Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α- induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.
AB - High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocytemacrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro. Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α- induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.
KW - Bone resorption
KW - Cytokine
KW - Infectious disease
KW - Molecular imaging
KW - Periodontal disease
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U2 - 10.1128/IAI.00111-18
DO - 10.1128/IAI.00111-18
M3 - Article
C2 - 29531138
AN - SCOPUS:85045952280
VL - 86
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 5
M1 - e00111-18
ER -