TNF biology, pathogenic mechanisms and emerging therapeutic strategies

Abstract

TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of 'short-term transcriptional memory'. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.

Figure 1. Signalling modalities and bioactivities downstream of TNF receptors

a | TNF receptor 1 (TNFR1) signalling is activated by both soluble and transmembrane TNF. TNFR1 bears a death domain that recruits the adaptor protein TNFR1-associated death domain protein (TRADD). Ligation of TNFR1 by soluble TNF or transmembrane TNF leads initially to the assembly of complex I, which activates nuclear factor κB (NFκB) and mitogen-activated protein kinases (MAPKs). TNFR1–complex I signalling induces inflammation, tissue degeneration, cell survival and proliferation, and orchestrates the immune defence against pathogens. Alternative signalling modalities, associated with programmed cell death, can also be activated downstream of TNFR1. The formation of the complexes IIa and IIb (also known as ripoptosome) results in apoptosis, whereas complex IIc (necrosome) induces necroptosis and inflammation. b | TNFR2 is proposed to be fully activated primarily by transmembrane TNF, in the context of cell-to-cell interactions. TNFR2 recruits TNFR-associated factor 2 (TRAF2) via its TRAF domain, triggering the formation of complex I and the downstream activation of NFκB, MAPKs and AKT. TNFR2 mediates primarily homeostatic bioactivities including tissue regeneration, cell proliferation and cell survival. This pathway can also initiate inflammatory effects and host defence against pathogens. MLKL, mixed lineage kinase domain-like protein.

Figure 2. A model of TNFR–complex I signalling

The binding of homotrimeric TNF to homotrimeric TNF receptors (TNFRs) induces the formation of complex I, comprising TNFR1-associated death domain protein (TRADD), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1) or cIAP2, and linear ubiquitin chain assembly complex (LUBAC). cIAPs and LUBAC decorate RIPK1 with scaffolding Lys63-linked and Met1-linked polyubiquitin chains, inducing the recruitment of transforming growth factor (TGF)-β-activated kinase 1 (TAK1) and inhibitor of κB (IκB) kinase (IKK) complexes. TAK1 activates p38 and JUN N-terminal kinase (JNK), leading to the transcription of AP1-target genes. IKKβ phosphorylates IκB, inducing its proteasomal degradation and the release of nuclear factor κB (NFκB). Free NFκB translocates to the nucleus, where it induces the expression of target genes. NEMO, NFκB essential modulator; TAB, TAK1-binding protein.

Figure 3. Molecular mechanisms of the differential induction kinetics of TNF-inducible genes

a | Immediate early TNF-inducible genes have an accessible chromatin state, which enables the unopposed and rapid recruitment of nuclear factor κB (NFκB). b | Induction of genes that have inaccessible chromatin (due to the presence of a chromatin barrier, such as nucleosomes) by TNF is delayed, as it requires chromatin remodelling to remove the chromatin barrier and enable the recruitment of NFκB. c | For one class of de novo protein synthesis-dependent genes, TNF first induces the production of IFN-β, which subsequently functions in an autocrine manner to activate signal transducer and activator of transcription (STAT) signalling. Eventually, STATs cooperate with TNF-induced NFκB for the optimal induction of genes. d | For another class of de novo protein synthesis-dependent genes dependent on IκBζ production, TNF-induced IκBζ is recruited to the promoter by NFκB and operates as a co-activator to trigger gene-induction. e | The induction by TNF of transcription of repressed genes is prevented by the presence of a co-repressor complex. A well-known co-repressor is nuclear receptor co-repressor 1 (NCoR), which recruits histone deacetylase 3 (HDAC3) that removes acetyl groups from neighbouring histones, creating a chromatin environment that is inaccessible to NFκB. The NCoR complex is recruited to methylated CpG motifs via the adaptor protein methyl-CpG-binding protein 2 (MeCP2). TNFR, TNF receptor.

Figure 4. TNF modulates cellular responses to subsequent challenges and imposes short-term memory

a | TNF-induced cell priming (sensitization). Prolonged exposure to TNF primes the chromatin of fibroblast-like synoviocytes (FLS) in a gene-specific manner, by histone eviction, acetylation of the remaining histones, and loading of nuclear factor κB (NFκB) to specific interferon (IFN)-target genes. In addition, TNF induces the expression of signal transducer and activator of transcription 1 (STAT1), increasing the intracellular STAT1 reservoir. This ‘primed’ state is maintained for several days, imposing a ‘short-term memory’ in cells. Primed FLS display hyperresponsiveness to saturating doses and sensitization to suboptimal doses of IFNs. b | TNF-induced cell tolerization (desensitization). TNF induces a ‘tolerized’ state in macrophages by triggering the expression of A20 via a glycogen synthase kinase 3β (GSK-3β)-dependent mechanism, and by establishing a gene-specific chromatin barrier. A20 attenuates the signalling input and the chromatin barrier prevents gene-expression upon subsequent stimulation with lipopolysaccharide (LPS). TLR, Toll-like receptor.