Chapter 18 - The role of YY1 in the pathogenesis of rheumatoid arthritis: A tale of cytokines, ncRNAs, and aberrant fibroblast-like synoviocytes (FLSs)

Abstract

Rheumatoid arthritis (RA) presents a continued strain on modern healthcare and economic systems. The molecular factors driving the rampant inflammatory response in RA add layers of complexity to our understanding of RA pathogenesis. From the time of onset to disease progression, the abnormal cytokine landscape converts both immune cells and stromal cells in the synovial joint to proinflammatory phenotypes that promote cartilage and bone damage. Recently, sets of microRNAs (miRNA) and long noncoding RNAs (lncRNA) have given additional clues as to how RA-associated fibroblast-like synoviocytes (RAFLSs) influence the divergence from normal joint homeostasis. Through integrating data on the various impacts of critical effector pathways, such as the NF-κB pathway, we may reinforce our knowledge of the forces behind persistent local and systemic autoimmunity. Emerging evidence supports a pathogenic role for the multifunctional transcription factor Yin Yang 1 (YY1) in RA. YY1 is best known for its importance in regulating key development processes and tumorigenesis. Reported studies have described interactions between YY1 and various pathways known to amplify cytokine production in peripheral blood mononuclear cells (PBMCs) and enhance the “tumor-like” qualities of RAFLSs. In this chapter, we reviewed the literature implicating YY1 in various aspects of the pathophysiology of RA and have proposed two putative pathways that may link disparate findings into a cohesive network: the TNF-α/NF-κB/YY1/ANRIL/miR-122-5p axis and the TNF-α/Notch1/YY1/c-myc axis. Accordingly, we have added YY1 to the repertoire of potential therapeutic targets that, when inhibited, may hamper the chronic inflammatory response in RA.