Tumour necrosis factor signalling in health and disease

Abstract

The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involvement as well as cellular activation with subsequent proliferation and programmed cell death or necrosis. As might be expected with such a broad spectrum of cellular effects and complex signalling pathways, TNF has also been implicated in a number of disease states, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. Since the time of its discovery over 40 years ago, TNF ligand and its receptors, TNF receptor (TNFR) 1 and 2, have been categorised into two complementary superfamilies, namely TNF (TNFSF) and TNFR (TNFRSF), and 19 ligands and 29 receptors have been identified to date. There have been significant advances in our understanding of TNF signalling pathways in the last decade, and this short review aims to elucidate some of the most recent advances involving TNF signalling in health and disease.

Keywords: Autoinflammatory; Cell death; Immunometabolism; TNF; TNFR.

Figure 1.. Overview of tumour necrosis factor (TNF): TNF receptor 1/2 (TNFR1/2) signalling pathways.

Both soluble TNF (sTNF) and membrane TNF (mTNF) activate TNFR1. TNFR1 contains a death domain which interacts with TNFR1-associated death domain (TRADD). Depending on the ubiquitination state of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), the cell undergoes apoptosis (via complexes IIa and IIb), necrosis (via complex IIc), or cell survival (via complex I). The formation of complexes IIa and IIb leads to the cleavage of pro-caspase-8 to form caspase-8 and induction of apoptosis. When complex IIc forms, the mixed lineage kinase domain-like protein (MLKL) is activated, inducing necroptosis. Upon the formation of complex I, cell survival is induced via the activation of nuclear factor-kappa B (NF-κB) and AP1 transcription factors because of RIPK1 ubiquitination. TNFR2, however, is activated primarily by mTNF and does not contain an intracellular death domain but interacts directly with TNFR-associated factor (TRAF) 1 and 2 to induce the formation of complex I with induction of homeostatic signals.

Figure 2.. Overview of the tumour necrosis factor receptor 1 (TNFR1) signalling pathway.

In the binding of TNF to TNFR1, TNFR1 recruits the TNFR1-associated death domain (TRADD), which then binds to receptor-interacting serine/threonine-protein kinase 1 (RIPK1), TNFR-associated factor 2 or 5 (TRAF2/5), and cellular inhibitor of apoptosis protein 1 or 2 (cIAP1/2) to form complex I. cIAP1/2 and the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIP, HOIL, and SHARPIN, add Met1-linked and Lys63-linked polyubiquitin chains, respectively, to RIPK1. This stabilises RIPK1, amplifying its signal. Lys63-linked chains on RIPK1 recruit the transforming growth factor-beta (TGFβ)-activated kinase 1 (TAK1) complex, consisting of TGFβ-activated kinase 1 and mitogen-activated protein kinase (MAPK)-binding protein 2 and 3 (TAB2 and 3) and TAK1. The TAK1 complex phosphorylates MAPK, Jun N-terminal kinase (JNK), and the IκB kinase (IKK) complex. This results in the translocation of transcription factors AP1 and nuclear factor-kappa B (NF-κB) into the nucleus, leading to the transcription of target genes. RIPK1 is deubiquitinated by cylindromatosis tumour suppressor protein deubiquitinase (CYLD), facilitating its dissociation from complex I to form complex IIb, consisting of RIPK1, RIPK3, FAS-associated death domain (FADD), caspase-8, and FLICE-like inhibitory protein long (cFLIP _L). cFLIP _L regulates both the apoptosis and the necrosis pathway, preventing caspase-8 activation to avert apoptosis. cFLIP _L acts in complex with caspase-8 to cleave RIPK1 and RIPK3 to inhibit their aggregation and the activation of mixed lineage kinase domain-like protein (MLKL), which would result in necrosis. HOIL-1, heme-oxidised iron regulatory protein 2 ubiquitin ligase 1; HOIP, HOIL-1 interacting protein.