Mechanisms of TNFα regulation in uveitis: Focus on RNA-binding proteins

Tumour necrosis factor-α (TNFα) is a key mediator of inflammation and plays a crucial role during the early phase of a host’s defence against bacterial, viral and parasitic infections. Persistent production of TNFα occurs in many autoimmune inflammatory diseases, including uveitis, and this is associated with significant tissue damage. Although uveitis represents a phenotypically heterogeneous group of intraocular inflammatory conditions, they have in common raised levels of TNFα in both serum and aqueous humour. Supporting a critical role for TNF activity during uveitis are reports that serum levels of TNFα correlate with disease status as well as the increasing evidence of therapeutic success of anti-TNF agents. TNFα is an archetypal pleiotropic cytokine and when acting systemically acute release may cause profound physiological decompensation. Yet, conversely, at tissue sites TNFα plays important roles governing homeostasis and during chronic inflammation regulating immune responses through control of, for example, macrophage-T cell functions. In a murine model of CD4 + T cell mediated non-infectious uveitis, experimental autoimmune uveitis (EAU), activation of infiltrating macrophages mediates tissue damage. In EAU, whilst both T cells and macrophages generate TNFα, tissue damaging macrophage activation is dependent upon TNF receptor 1 (p55). TNFα protein production is controlled at the level of transcription, pre-mRNA processing, mRNA stability, translation and retention at the plasma membrane. The p38 MAP kinase and MAPKAP-2 pathway are involved in the post-transcriptional regulation of TNFα and are targeted by a functionally divergent group of cytokines including IL-10 and TGFβ1. Common to many cytokines, TNFα mRNA 3′ untranslated region (UTR) contains an AU-rich element (ARE), which drives repression by mRNA-binding proteins (RBPs). These include tristetraprolin (TTP), T cell antigen-1 (TIA-1), TIA-1-related protein (TIAR), human antigen R (HuR) and fragile-X-related protein 1 (FXR1). Disruption of several RBPs can dysregulate TNFα protein production and has, in some cases, been shown to exacerbate chronic inflammatory disease both in mice and in humans. Given that TNFα is central to clearance of infections, yet during chronic inflammation results in tissue damage, understanding the role that RBPs play in the control of TNFα may give rise to opportunities to not only develop targeted therapy for autoimmunity but also redress homeostasis without com