Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of multiple synovial joints, and leads to bone and cartilage destruction. Natural killer T (NKT) cells act as a link between innate and adaptive immunity because they are able to activate a variety of immune cells. A previous study conducted using murine models showed that NKT cells have the unique property of enhancing osteoclast progenitor and precursor development. However, the role play by NKT cells in inflammatory bone destruction, such as that associated with RA, remains unknown.
Objectives The aims of the present study were to investigate the role of NKT cells during osteoclastogenesis, the mechanism underlying the dysregulation of osteoclastogenesis in RA, and the in vivo effect of α-galactosylceramide (αGalCer)-stimulated NKT cells in a mouse model of collagen-induced arthritis (CIA).
Methods Patients with RA (n=25) and healthy controls (n=12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of M-CSF and receptor activator of nuclear factor kB ligand (RANKL). PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in collagen-induced arthritis (CIA) mice.
Results In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls, but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-γ production, in a cytokine-dependent manner (not by cell-cell contact), and down-regulated osteoclast-associated genes. aGalCer-treated mice showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by aGalCer treatment.
Conclusions This study primarily demonstrates that aGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect on inflammatory bone destruction. However, it also shows that these effects of aGalCer are diminished in RA patients, and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA.
Hu M, Bassett JH, Danks L, Howell PG, Xu K, Spanoudakis E, et al. Activated invariant NKT cells regulate osteoclast development and function. J Immunol 2011;186:2910-7.
Tudhope SJ, von Delwig A, Falconer J, Pratt A, Woolridge T, Wilson G, et al. Profound invariant natural killer T-cell deficiency in inflammatory arthritis. Ann Rheum Dis 2010;69:1873-9.
Acknowledgements This study was supported by a grant from the National Research Foundation of Korea funded by the Korean Government (#2013R1A2A2A01067956).
Disclosure of Interest None declared