Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?

Abstract

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.

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

“…Thus, p100 silencing may exhibit mixed anti-and proinflammatory effects. In the future, we plan to explore selective inhibition of NF-κB-inducible kinase as this is the most important regulatory kinase of the noncanonical pathway (40).…”

The non-canonical NF-κB pathway in immunity and inflammation

“…The pathogenesis of RA involves the recruitment of innate immune cells and inflammatory T cells, particularly T H 17 cells, to the synovial tissue, where they release pro-inflammatory cytokines and induce synovitis. Canonical NF-κB signalling has long been recognized for its pro-inflammatory role in RA, but strong evidence suggests that non-canonical NF-κB signalling is also involved in different aspects of RA pathogenesis 136 . The aetiology of RA is linked to several TNF and TNFR superfamily members known to mediate non-canonical NF-κB activation 137 .…”

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

“…Similarly, ADM also remained impaired in LTp21 −/− mice (figure 5D). As non-canonical NF-κB signalling can also regulate cell proliferation,31 we assessed NF-κB activation at this time point as well (figure 5F). The activation of canonical NF-κB remains insignificant (see online Supplementary figure 7A), while non-canonical NF-κB signalling in LT animals was highly activated as published previously 24.…”

“…Later, infiltrating cells that were attracted through non-NF-κB-dependent mechanisms contributed to the inflammatory gene expression, inducing further inflammatory cell accumulation. Furthermore, the decreased RelB nuclear translocation in the LTp21 −/− acinar cells could be linked to the impairment of proliferation as the non-canonical NF-κB signalling was previously shown to regulate proliferation and survival in various cell types, for example, B cells and plasma cells 31. Our data therefore suggest that p21 enables LT-induced non-canonical NF-κB activation, as a way of transmitting the inflammatory stimuli, which could have broader implications in various inflammatory syndromes.…”