The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis.

Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1ß, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP+ osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.

Polysaccharides from European Black Elderberry Extract Enhance Dendritic Cell Mediated T Cell Immune Responses.

European black elderberry (Sambucus nigra L.) is a popular way to treat common colds or influenza infections. Mechanistically, this might be due to a direct antiviral effect or a stimulatory effect on the immune system of the host. Here, we evaluated the modulatory effects of black elderberry derived water extract (EC15) and its polysaccharide enriched fractions (CPS, BOUND, and UNBOUND) in comparison to a conventional alcoholic extract (EE25), regarding the phenotypical and functional properties of dendritic cells (DCs), which are essential cells to induce potent T cell responses. Interestingly, the water extract and its polysaccharide fractions potently induced DC maturation, while the ethanol extract did not. Moreover, the capacity to stimulate T cells by these matured DCs, as assessed using MLR assays, was statistically higher when induced by the water extracted fractions, compared to immature DCs. On the other hand, the ethanol extract EE25 did not induce T cell stimulation. Finally, the cytokine expression profiles of these DC-T cell cocultures were assessed and correlated well with increased T cell stimulation. Also, the expression of inflammatory cytokines, such as IL-6, TNF-α, and IFN-γ was highly increased in the presence of the elderberry water extract EC15, and the polysaccharide enriched CPS, BOUND, and UNBOUND fractions, but not by EE25. Thus, from these data, we conclude that the polysaccharides present in water-derived elderberry fractions induce potent immune-modulatory effects, which represents the basis for a strong immune-mediated response to viruses including influenza.