Possible pathogenic engagement of soluble Semaphorin 4D produced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ)
| Autor: | Sook-Bin Woo, Alessandro Villa, Hajime Sasaki, Jae Young Kim, Kenji Egashira, Tomomi Kiyama, Alexandru Movila, Toshihisa Kawai, Hani Mawardi, Kazuaki Nishimura |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Biophysics SEMA4D Pamidronate Semaphorins Biochemistry Zoledronic Acid Pathogenesis Lesion 03 medical and health sciences Antigens CD Medicine Animals Humans Molecular Biology Mice Knockout Diphosphonates business.industry Multiple sclerosis Imidazoles Antibodies Monoclonal Receptors Antigen T-Cell gamma-delta Cell Biology Middle Aged medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Rheumatoid arthritis Immunology Systemic administration Tumor necrosis factor alpha Bisphosphonate-Associated Osteonecrosis of the Jaw Female medicine.symptom business Osteonecrosis of the jaw |
| Zdroj: | Biochemical and biophysical research communications. 480(1) |
| ISSN: | 1090-2104 |
| Popis: | Prior consensus held that medication-related osteonecrosis of the jaw (MRONJ) lesion was composed of necrotic bone; however, more recent studies have identified inflammatory infiltrates in the lesion. Herein, we report that remarkably elevated infiltrating γδT cells (90% of lymphocytes) express Semaphorin 4D (Sema4D) in human patient with MRONJ lesion, whereas γδT cells only account for 2-5% of lymphocytes in blood. Importantly, Sema4D is implicated in the pathogenesis of T cell-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Indeed, in a mouse model of MRONJ, an elevated number of γδT, but not αβT, cells infiltrating in the MRONJ-like lesion was observed. Both elevated soluble Sema4D (sSema4D) production accompanied by pro-inflammatory cytokines, including TNF-α IFN-γ and IL-1β, and Sema4D-expressing γδT cells were detected in mouse MRONJ-like lesion. Activated γδT cells produced sSema4D in vitro, which could promote TNF-α production from macrophages. Meanwhile, γδT cell-KO mice were resistant to the induction of MRONJ and, hence, showed no elevation of local productions of Sema4D and TNF-α. Finally, systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of MRONJ in wild-type mice in conjunction with diminished level of TNF-α. These results suggested a critical pathogenic engagement of Sema4D produced by γδT cells in the development of MRONJ. |
| Databáze: | OpenAIRE |
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