title: TRAP-positive osteoclast precursors mediate ROS/NO-dependent bactericidal activity via TLR4.
abstract: Osteoclastogenesis was induced by RANKL stimulation in mouse monocytes to examine the possible bactericidal function of osteoclast precursors (OCp) and mature osteoclasts (OCm) relative to their production of NO and ROS. Tartrate-resistant acid phosphatase (TRAP)-positive OCp, but few or no OCm, phagocytized and killed Escherichia coli in association with the production of reactive oxygen species (ROS) and nitric oxide (NO). Phagocytosis of E. coli and production of ROS and NO were significantly lower in TRAP+ OCp derived from Toll-like receptor (TLR)-4 KO mice than that derived from wild-type (WT) or TLR2-KO mice. Interestingly, after phagocytosis, TRAP+ OCp derived from wild-type and TLR2-KO mice did not differentiate into OCm, even with continuous exposure to RANKL. In contrast, E. coli-phagocytized TRAP+ OCp from TLR4-KO mice could differentiate into OCm. Importantly, neither NO nor ROS produced by TRAP+ OCp appeared to be engaged in phagocytosis-induced suppression of osteoclastogenesis. These results suggested that TLR4 signaling not only induces ROS and NO production to kill phagocytized bacteria, but also interrupts OCm differentiation. Thus, it can be concluded that TRAP+ OCp, but not OCm, can mediate bactericidal activity via phagocytosis accompanied by the production of ROS and NO via TLR4-associated reprograming toward phagocytic cell type.
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; Tohoku University Hospital, Maxillo-oral Disorders, Sendai, Japan. Electronic address: knishimura@dent.tohoku.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; The University of Tokushima Graduate School, Department of Conservative Dentistry, Institute of Health Biosciences, Tokushima, Japan. Electronic address: c301351004@tokushima-u.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shindo
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA. Electronic address: amovila@forsyth.org.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Movila
authors.affiliation: King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia. Electronic address: rkayal@kau.edu.sa.
authors.forename: Rayyan
authors.initials: R
authors.lastname: Kayal
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia. Electronic address: albassam.a@hotmail.com.
authors.forename: Albassam
authors.initials: A
authors.lastname: Abdullah
authors.affiliation: Airlangga University, Department of Periodontics, Jawa Timur, Indonesia. Electronic address: irmaudijanto@gmail.com.
authors.forename: Irma Josefina
authors.initials: IJ
authors.lastname: Savitri
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA. Electronic address: aikeda@forsyth.org.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; Research and Development Headquarters, LION Corporation, 100 Tajima Odawara, Kanagawa, Japan. Electronic address: tsuguno@gmail.com.
authors.forename: Tsuguno
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia. Electronic address: mhowait@icloud.com.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Howait
authors.affiliation: King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia. Electronic address: aaldharab@kau.edu.sa.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Dharrab
authors.affiliation: King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia. Electronic address: amira@kau.edu.sa.
authors.forename: Abdulghani
authors.initials: A
authors.lastname: Mira
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA. Electronic address: XHan@forsyth.org.
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Han
authors.affiliation: The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA. Electronic address: tkawai@forsyth.org.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D004926:Escherichia coli / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050296:Microbial Viability; D009569:Nitric Oxide / Q000502:physiology*; D010010:Osteoclasts / Q000378:metabolism* / Q000382:microbiology; D010587:Phagocytosis; D053245:RANK Ligand / Q000502:physiology; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D053245:RANK Ligand; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; C505689:Tnfsf11 protein, mouse; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Bacteria; Nitric oxide; Osteoclast; Phagocytosis; RANKL; Reactive oxygen species; Tartrate-resistant acid phosphatase; Toll-like receptor