Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?
Bottom Line: NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway.It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA).In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.
The nuclear factor-κB (NF-κB) family of transcription factors is essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway. It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA). Although less extensively studied, the non-canonical NF-κB pathway is not only central in lymphoid organ development and adaptive immune responses, but is also thought to play an important role in the pathogenesis of RA. Importantly, this pathway appears to have cell type-specific functions and, since many different cell types are involved in the pathogenesis of RA, it is difficult to predict the net overall contribution of the non-canonical NF-κB pathway to synovial inflammation. In this review, we describe the current understanding of non-canonical NF-κB signaling in various important cell types in the context of RA and consider the relevance to the pathogenesis of the disease. In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects.
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Mentions: The studies reviewed above support the role of the non-canonical NF-κB pathway as a major participant in inflammatory responses in general and the pathogenesis of RA in particular. NIK and downstream non-canonical NF-κB signaling have diverse functions, depending on the cell types in which this pathway is activated. Roughly, in synovial fibroblasts, osteoclasts, endothelial cells, and B cells/plasma cells, non-canonical NF-κB signaling contributes to the inflammatory process by triggering the secretion of critical inflammatory mediators and matrix-degrading enzymes involved in tissue degradation, whereas in macrophages, dendritic cells and T cells this pathway has more pleiotropic functions and can also play a more regulatory, anti-inflammatory role (Figure 2). In these cells non-canonical NF-κB signaling shows clear resemblance with ‘The Strange Case of Dr Jekyll and Mr Hyde’ (Robert Louis Stevenson): there is a good and an evil side. Further elucidation of the precise function of this pathway in individual cell types will result in a better understanding of the overall contribution of the non-canonical NF-κB pathway to the complex cellular networks involved in RA synovial inflammation. This will allow the design of better therapeutic strategies for the management of this disease, including cell type-specific inhibitors or selective targeting of inhibitors to certain cell types. For this application, anti-DEC-205 antibodies may be used to target compounds specifically to DCs or to selectively target ECs, and (peptide) inhibitors can be coupled to a multimodular recombinant protein that specifically binds to cytokine-activated endothelium, which has been demonstrated to work very elegantly under inflammatory conditions in vivo .Figure 2