Death by TNF: a road to inflammation

Abstract

Tumour necrosis factor (TNF) is a central cytokine in inflammatory reactions, and biologics that neutralize TNF are among the most successful drugs for the treatment of chronic inflammatory and autoimmune pathologies. In recent years, it became clear that TNF drives inflammatory responses not only directly by inducing inflammatory gene expression but also indirectly by inducing cell death, instigating inflammatory immune reactions and disease development. Hence, inhibitors of cell death are being considered as a new therapy for TNF-dependent inflammatory diseases.

Fig. 1. Timeline of key events in the history of TNF and TNF-induced cell death.

IKK, inhibitor of nuclear factor-κB kinase; MLKL, mixed lineage kinase domain-like protein; NF-κB, nuclear factor-κB; RA, rheumatoid arthritis; RIPK, receptor-interacting serine/threonine protein kinase; TNF, tumour necrosis factor; TNFR, tumour necrosis factor receptor.

Fig. 2. Inflammatory signalling by TNFR1.

a, Binding of tumour necrosis factor (TNF) to TNF receptor 1 (TNFR1) directly promotes inflammation by activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways, which collectively lead to the transcriptional upregulation of genes encoding proinflammatory mediators, such as cytokines and chemokines. b, TNFR1 activation also indirectly promotes inflammation by triggering cell death. Lytic forms of cell death, such as apoptosis-driven secondary necrosis, pyroptosis and necroptosis, release damage-associated molecular patterns (DAMPs) that activate proinflammatory gene expression in bystander cells. In addition, the inflammatory response may originate from and/or be amplified by loss of barrier function caused by epithelial cell death (lytic and non-lytic) and the subsequent sensing of pathogen-associated molecular patterns (PAMPs) from microorganisms that have breached the epithelial barrier. PRR, pattern recognition receptor.

Fig. 3. Signalling by TNFR1 and overview of the three characterized cell death checkpoints in the TNFR1 pathway.

a, Sensing of tumour necrosis factor (TNF) by TNF receptor 1 (TNFR1) leads to the formation of a primary membrane-bound receptor signalling complex (complex I) that activates the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signalling pathways, leading to proinflammatory gene expression. A secondary, potentially cytotoxic, cytosolic complex (complex II) originates from the dissociation of complex I components from the receptor, and from their association with FAS-associated death domain-containing protein (FADD) and caspase 8. Three cell death checkpoints actively repress TNF cytotoxicity. First, the inhibitor of nuclear factor-κB kinase (IKK) checkpoint consists of the inhibition of receptor-interacting serine/threonine protein kinase 1 (RIPK1) kinase activity through phosphorylation mediated by complexes of IKKα and IKKβ and TANK-binding kinase 1 (TBK1) and IKKε. Second, the NF-κB checkpoint, which consists of the NF-κB-dependent transcriptional upregulation of prosurvival genes (including the gene encoding FLICE-like inhibitory protein (FLIP)). Third, the caspase 8 checkpoint, which consists of RIPK1 inactivation by caspase 8-mediated cleavage. b, Inhibition of the IKK checkpoint leads to activation of RIPK1 in complex I, and the subsequent kinase-dependent assembly of complex IIb, which drives apoptosis or pyroptosis depending on the cellular context. Of note, conditions that affect proper IKKα–IKKβ activation will additionally inactivate the NF-κB checkpoint. c, Conditions leading to inactivation of the NF-κB checkpoint, such as the in vitro use of the translation inhibitor cycloheximide, activate complex IIa and result in RIPK1 kinase activity-independent apoptosis. d, Inhibition of the caspase 8 checkpoint induces RIPK1 cytotoxicity by the kinase-dependent assembly of complex IIb and the necrosome. TNF sensing in caspase 8-inhibited conditions will result only in necroptosis induction. Additional checkpoints may exist. cIAP, cellular inhibitor of apoptosis protein; GSDMD, gasdermin D; LUBAC, linear ubiquitin chain assembly complex; NAP1, NAK-associated protein 1; NEMO, NF-κB essential modulator; TAB, TGFβ-activated kinase 1-binding protein; TAK1, TGFβ-activated kinase 1; TANK, TRAF family member-associated NF-κB activator; TRADD, TNFR1-associated death domain protein; TRAF2, TNFR-associated factor 2; Ub, ubiquitin.