Regulation of dendritic cell survival and cytokine production by osteoprotegerin

Abstract

The TNF family ligand, RANKL, and its two TNFR family receptors, RANK and OPG, enable coordinated regulation between the skeletal and immune systems. Relatively little is known about how OPG influences RANKL-RANK interactions for the regulation of DCs. Here, we show that OPG KO bone marrow-derived DCs survive better and produce more TNF-alpha, IL-12p40, and IL-23 in response to Escherichia coli LPS than WT DCs. RANKL is induced on DCs within 24 h after LPS stimulation. OPG limits RANKL-RANK interactions between DCs, which can promote DC survival and elevated expression of proinflammatory cytokines. Survival of and cytokine production by OPG KO DCs are inhibited by soluble OPG; conversely, anti-OPG enhances survival and cytokine production by WT DCs. Bim KO DCs, like OPG KO, also survive longer and produce more TNF-alpha than WT DCs; however, unlike OPG KO, Bim KO DCs do not produce more IL-23. In addition, after inoculation with LPS, OPG KO mice produce more TNF-alpha and IL-12p40 than WT mice but not more IL-6. Thus, OPG regulates not only DC survival but also the nature of DC-dependent inflammatory responses.

Osteoprotegerin, but not osteopontin, as a potential predictor of vascular calcification in normotensive subjects

“…OPG, a vascular calcification inhibitor, is upregulated when an inflammation process develops. 26 Despite our not observing an increase in CRP levels with respect to the CAC score categories, a significant correlation between CRP and OPG was visible. Vascular calcification is a multistep process that is initiated by the differentiation of vascular cells of mesenchymal origin to osteoblast-like cells in atherosclerotic regions.…”

“…The probable mechanism involves dendritic cell survival and expression of proinflammatory cytokines. 26 However, this process is likely masked by different stimuli in hypertensive patients, which enhance OPG expression even in patients with zero or minimal CAC. 27 It was previously observed that higher OPG concentrations were associated with an increased risk of all-cause mortality (odds ratio 1.39 (1.04-1.85)) and cardiovascular mortality (odds ratio 1.83 (1.10-3.05)).…”

“…OPG limits the interaction between receptor activator of nuclear factor k-B ligandreceptor and activator of nuclear factor k-B that takes place between dendritic cells, which can promote their survival and the elevated expression of proinflammatory cytokines. 26 This process is regulated by the same pathways that mediate vascular inflammation and endothelial dysfunction. 5,22 It is possible that the role of fibrinogen in vascular calcification is strictly associated with inflammation.…”

Dendritic Cell Apoptosis: Regulation of Tolerance versus Immunity

“…Another receptor to which TRANCE binds is osteoprotegerin (OPG), which functions as a decoy receptor. OPG 2/2 DCs have better survival than wild type DCs, which is likely due to the absence of OPG in limiting TRANCE-RANK interactions (18).…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…6 Immature circulating DCs can survive up to 10-14 d in vivo, with the lifespan of myeloid DCs being relatively shorter than that of plasmacytoid DCs. 7,8 DC maturation is induced by a number of factors including TNF-a, CpG, Poly I:C, and LPS. 9 The mature DCs stimulate the adaptive immune system by presentation of foreign antigen in the context of MHC I or MHC II to naive CD8 C or CD4 C T cells respectively, causing them to become activated.…”