Abstract
Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic.
Highlights
Common chronic inflammatory and autoinflammatory diseases are caused by immune dysregulation, the aetiology of which involves a complex interplay between genetic and environmental factors that is incompletely understood [1]
Both RIPK1 kinase dead mice and mice receiving the RIPK1 kinase inhibitor, GNE684, were shown to have reduced acute innate immune cell-driven collagen antibody-induced arthritis (CAIA). This effect was directly attributable to GNE684 inhibiting Tumour necrosis factor (TNF) signalling, as blocking TNF using TNFR2-Fc caused an equivalent effect and failed to further dampen responses upon co-therapy [135]. These results suggest that RIPK1 kinase inhibitors are likely to be as efficacious as TNF biologicals for the treatment of Rheumatoid arthritis (RA)
intestinal epithelial cell (IEC) (Villin cre) results in spontaneous colitis mediated by tumour necrosis factor receptor-1 (TNFR1) signalling and RIPK1 kinase-dependent cell death [135,184,185], while IKKβ protects against colitis induced by Clostridium difficile or dextran sodium sulphate (DSS) [186,187]
Summary
Common chronic inflammatory and autoinflammatory diseases are caused by immune dysregulation, the aetiology of which involves a complex interplay between genetic and environmental factors that is incompletely understood [1]. Tumour necrosis factor (TNF) is the archetypal death ligand and a pivotal pathogenic cytokine in many common inflammatory diseases. RIPK1 has a critical scaffolding role in tumour necrosis factor receptor-1 (TNFR1) and Toll-like receptor 3/4 (TLR3/4) pro-inflammatory signalling [5,6,7], as well as a kinase-dependent role in both apoptotic and necroptotic cell death [8]. The carboxy-terminal death domain (DD) of RIPK1 can facilitate its interaction with other DDcontaining proteins to promote formation of death receptor signalling complexes [9,10,11], while its RIP homotypic interaction motif (RHIM) domain ( shared with RIPK3) enables. E3ubiquitin ubiquitin ligase ligase activity of apoptosis proteins (cIAP)-1 of cIAP1/2. Inflammation mediated by unrestrained apoptosis and necroptosis [30,31,32,33,34,35,36]
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