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.
Highlights
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, which can be generated in most mammalian cells by various stimuli [1, 2]
To determine the role of Sphingosine-1-phosphate receptor 2 (S1PR2) in proinflammatory cytokine production induced by bacterial pathogen, bone marrow-derived monocytes and macrophages (BMMs) derived from C57BL/6J mice were untreated, treated with a S1PR2 small hairpin RNA (shRNA) lentiviral vector, or treated with a control shRNA lentiviral vector
S1PR2 shRNA decreased S1PR2 mRNA expression, which subsequently suppressed IL-1β, IL-6, and TNF-α protein generation induced by the oral pathogen A. actinomycetemcomitans
Summary
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, which can be generated in most mammalian cells by various stimuli [1, 2]. Our previous study demonstrated that Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), an oral pathogen associated with localized aggressive periodontitis, stimulated the generation of S1P in RAW 264.7 cells, a murine macrophage cell line [3]. We demonstrated that reduction in generation of S1P in sphingosine kinase 1-deficient mice attenuated periodontal inflammation and reduced alveolar bone loss induced by A. actinomycetemcomitans compared with wild type mice [4]. It is known that oral pathogens cause inflammatory bone loss, the cell signaling pathways that regulate the inflammatory bone loss response have not been completely elucidated.
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