title: IL-33 Exacerbates Periodontal Disease through Induction of RANKL.
abstract: Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor κB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis.
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.
authors: J
authors: J
authors: Malcolm
authors: Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
authors: R A
authors: RA
authors: Awang
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.
authors: J
authors: J
authors: Oliver-Bell
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK Institute of Biomedical and Environmental Health Research, School of Science, University of the West of Scotland, Paisley, United Kingdom.
authors: J P
authors: JP
authors: Butcher
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
authors: L
authors: L
authors: Campbell
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
authors: A
authors: A
authors: Adrados Planell
authors: Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
authors: D F
authors: DF
authors: Lappin
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
authors: S Y
authors: SY
authors: Fukada
authors: Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
authors: C J
authors: CJ
authors: Nile
authors: Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
authors: F Y
authors: FY
authors: Liew
authors: Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK shauna.culshaw@glasgow.ac.uk.
authors: S
authors: S
authors: Culshaw
mesh_terms: D016301:Alveolar Bone Loss / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000539:Alveolar Process / Q000473:pathology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D016866:Bacteroidaceae Infections / Q000276:immunology; D055113:Chronic Periodontitis / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D005881:Gingiva / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008437:Maxilla / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053244:Osteoprotegerin / Q000494:pharmacology; D016966:Porphyromonas gingivalis / Q000276:immunology; D053245:RANK Ligand / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000032:analysis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D007074:Immunoglobulin G; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D053244:Osteoprotegerin; D053245:RANK Ligand; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse
keywords: OPG; Porphyromonas gingivalis; ST2; cytokines; gingiva; periodontitis