title: Sphingosine-1-Phosphate Receptor 2 Regulates Proinflammatory Cytokine Production and Osteoclastogenesis.
abstract: Sphingosine-1-phosphate receptor 2 (S1PR2) couples with the Gi, Gq, and G12/13 group of proteins, which modulate an array of cellular signaling pathways and affect immune responses to multiple stimuli. In this study, we demonstrated that knockdown of S1PR2 by a specific S1PR2 shRNA lentiviral vector significantly inhibited IL-1β, IL-6, and TNF-α protein levels induced by oral pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) in murine bone marrow-derived monocytes and macrophages (BMMs) compared with controls. In addition, knockdown of S1PR2 by the S1PR2 shRNA lentiviral vector suppressed p-PI3K, p-ERK, p-JNK, p-p38, and p-NF-κBp65 protein expressions induced by A. actinomycetemcomitans. Furthermore, bone marrow cells treated with the S1PR2 shRNA lentiviral vector inhibited osteoclastogenesis induced by RANKL compared with controls. The S1PR2 shRNA suppressed the mRNA levels of six osteoclastogenic factors including nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 (NFATc1), cathepsin K (Ctsk), acid phosphatase 5 (Acp5), osteoclast-associated receptor (Oscar), dendritic cells specific transmembrane protein (Dcstamp), and osteoclast stimulatory transmembrane protein (Ocstamp) in bone marrow cells. We conclude that S1PR2 plays an essential role in modulating proinflammatory cytokine production and osteoclastogenesis. Blocking S1PR2 signaling might be a novel therapeutic strategy to treat inflammatory bone loss diseases.
authors.affiliation: Department of Oral Health Sciences, Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Hong
authors.identifier: http://orcid.org/0000-0002-0930-6810
authors.initials: H
authors.lastname: Yu
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D055017:Monocyte-Macrophage Precursor Cells / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D010010:Osteoclasts / Q000166:cytology* / Q000276:immunology; D010012:Osteogenesis; D016871:Pasteurellaceae Infections / Q000276:immunology*; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha; C533955:sphingosine-1-phosphate receptor-2, mouse