Tumor necrosis factor receptor signaling (TNF receptor signaling)

Tumor necrosis factor receptor signaling refers to the intracellular pathways activated by the binding of TNF (tumor necrosis factor) to its two main receptors, TNFR1 (widely expressed) and TNFR2 (primarily on immune cells, neurons, and endothelial cells), which mediate diverse responses including inflammation, cell survival, proliferation, apoptosis, and necroptosis.[1][2][3] TNFR1 signaling forms complex I for pro-survival NF-κB and MAPK activation via RIPK1 ubiquitination and adaptors like TRADD, TRAF2, and cIAPs, but shifts to death complexes (IIa/IIb/IIc) under stress, involving caspases, FADD, and MLKL when checkpoints fail.[1][2] TNFR2 preferentially binds membrane-bound TNF, recruits TRAF2 directly for canonical and non-canonical NF-κB pathways promoting tissue regeneration and proliferation, and modulates TNFR1 via TRAF2 depletion.[1][2] Dysregulation contributes to chronic inflammation in autoimmune diseases like rheumatoid arthritis and psoriasis, as well as cancer progression via tumor microenvironment modulation and immunosuppression through PD-L1 upregulation.[1][2] Therapeutically, TNF inhibitors like infliximab and etanercept revolutionized treatment of inflammatory conditions by blocking ligand-receptor interaction, though challenges include infection risks and incomplete pathway specificity.[1][2] Ongoing research explores TNFR-specific modulation for better safety, such as TNFR2 agonists for neuroprotection or inhibitors for necroptosis in neurodegeneration.[1][2]

Other names

TNF signalingTNFR signalingTumor necrosis factor signaling

TNF inhibition (neutralization of TNF ligand preventing receptor binding), TNFR1/TNFR2 blockade (direct antagonism of receptors)